Tricyclic benzazepine vasopressin antagonists

ABSTRACT

Tricyclic compounds of the general Formula I: ##STR1## as defined herein which exhibit antagonist activity at V 1  and/or V 2  receptors and exhibit in vivo vasopressin antagonist activity, methods for using such compounds in treating diseases characterized by excess renal reabsorption of water, and processes for preparing such compounds.

The application is a continuation-in-part of application Ser. No.08/639,014, filed Apr. 24, 1996, which is a continuation-in-part of U.S.application Ser. No. 08/254,823, filed Jun. 13, 1994, now U.S. Pat. No.5,512,563, which is a continuation-in-part of application Ser. No.08/100,003, filed Jul. 29, 1993, now abandoned.

FIELD OF THE INVENTION

This invention relates to new tricyclic non-peptide vasopressinantagonists which are useful in treating conditions where decreasedvasopressin levels are desired, such as in congestive heart failure, indisease conditions with excess renal water reabsorption and inconditions with increased vascular resistance and coronaryvasoconstriction.

BACKGROUND OF THE INVENTION

Vasopressin is released from the posterior pituitary either in responseto increased plasma osmolarity detected by brain osmoreceptors ordecreased blood volume and blood pressure sensed by low-pressure volumereceptors and arterial baroreceptors. The hormone exerts its actionthrough two well defined receptor subtypes: vascular V₁ and renalepithelial V₂ receptors. Vasopressin-induced antidiuresis, mediated byrenal epithelial V₂ receptors, helps to maintain normal plasmaosmolarity, blood volume and blood pressure.

Vasopressin is involved in some cases of congestive heart failure whereperipheral resistance is increased. V₁ antagonists may decrease systemicvascular resistance, increase cardiac output and prevent vasopressininduced coronary vasoconstriction. Thus, in conditions with vasopressininduce increases in total peripheral resistance and altered local bloodflow, V₁ -antagonists may be therapeutic agents. V₁ antagonists maydecrease blood pressure, induce hypotensive effects and thus betherapeutically useful in treatment of some types of hypertension.

The blockade of V₂ receptors is useful in treating diseasescharacterized by excess renal reabsorption of free water. Antidiuresisis regulated by the hypothalamic release of vasopressin (antidiuretichormone) which binds to specific receptors on renal collecting tubulecells. This binding stimulates adenylyl cyclase and promotes thecAMP-mediated incorporation of water pores into the luminal surface ofthese cells. V₂ antagonists may correct the fluid retention incongestive heart failure, liver cirrhosis, nephrotic syndrome, centralnervous system injuries, lung disease and hyponatremia.

Elevated vasopressin levels occur in congestive heart failure which ismore common in older patients with chronic heart failure. In patientswith hyponatremic congestive heart failure and elevated vasopressinlevels, a V₂ antagonist may be beneficial in promoting free waterexcretion by antagonizing the action of antiduretic hormone. On thebasis of biochemical and pharmacological effects of the hormone,antagonists of vasopressin are expected to be therapeutically useful inthe treatment and/or prevention of hypertension, cardiac insufficiency,coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis,congestive heart failure, nephrotic syndrome, brain edema, cerebralischemia, cerebral hemorrhage-stroke, thrombosis-bleeding and abnormalstates of water rentention.

The following prior art references describe peptide vasopressinantagonists: M. Manning etal., J. Med. Chem., 35, 382(1992); M. Manninget al., J. Med. Chem., 35, 3895(1992); H. Gavras and B. Lammek, U.S.Pat. No. 5,070,187 (1991); M. Manning and W. H. Sawyer, U.S. Pat. No.5,055,448(1991); F. E. Ali, U.S. Pat. No. 4,766,108(1988); R. R. Ruffoloet al., Drug News and Perspective, 4(4), 217, (May)(1991). P. D.Williams et al., have reported on potent hexapeptide oxytocinantagonists J. Med. Chem., 35, 3905(1992)! which also exhibit weakvasopressin antagonist activity in binding to V₁ and V₂ receptors.Peptide vasopressin antagonists suffer from a lack of oral activity andmany of these peptides are not selective antagonists since they alsoexhibit partial agonist activity.

Non-peptide vasopressin antagonists have recently been disclosed, Y.Yamamura et al., Science, 252, 579(1991); Y. Yamamura et al., Br. J.Pharmacol, 105, 787(1992); Ogawa et al., (Otsuka Pharm Co., LTD.) EP0514667-A1; JP 04154765-A; EPO 382185-A2; and WO9105549. Ogawa et al,(Otsuka Pharm. Co.) EP 470514A disclose carbostyril derivatives andpharmaceutical compositions containing the same. Non-peptide oxytocinand vasopressin antagonist have been disclosed by Merck and Co.; M. G.Bock and P. D. Williams, EP 0533242A; M. G. Bock et al., EP 0533244A; J.M. Erb, D. F. Verber, P. D. Williams, EP 0533240A; K. Gilbert et al., EP0533243A.

Premature birth can cause infant health problems and mortality and a keymediator in the mechanism of labor is the peptide hormone oxytocin. Onthe basis of the pharmacological action of oxytocin, antagonists of thishormone are useful in the prevention of preterm labor, B. E. Evans etal., J. Med. Chem. 35, 3919 (1992), J. Med. Chem., 36, 3993 (1993) andreferences therein. The compounds of this invention are antagonists ofthe peptide hormone oxytocin and are useful in the control of prematurebirth.

The present invention relates to novel tricyclic derivatives whichexhibit antagonist activity at V₁ and/or V₂ receptors and exhibit invivo vasopressin antagonist activity. The compounds also exhibitantagonist activity at oxytocin receptors.

SUMMARY OF THE INVENTION

This invention relates to new compounds selected from those of thegeneral formula I: ##STR2## wherein Y is (CH₂)_(n), O, S, NH, NCOCH₃,N-lower alkyl (C₁ -C₃), CH-lower alkyl(C₁ -C₃), CHNH-lower alkyl (C₁-C₃), CHNH₂, CHN lower alkyl (C₁ -C₃)!₂, CHO-lower alkyl(C₁ -C₃),CHS-lower alkyl(C₁ -C₃), or the moiety: ##STR3## wherein n is an integerfrom 0-2; A-B is ##STR4## wherein m is an integer from 1-2, providedthat when Y is --(CH₂)_(n) -- and n=2, m may also be zero and when n iszero, m may also be three, provided also that when Y is --(CH₂)_(n) --and n is 2, m may not also be two.

R₁ is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH,--S-lower alkyl(C₁ -C₃), --SH, --SO lower alkyl(C₁ -C₃), --SO₂ -loweralkyl(C₁ -C₃), --CO-lower alkyl(C₁ -C₃), --CF₃ ; lower alkyl(C₁ -C₃);O-lower alkyl(C₁ -C₃), --NO₂, --NH₂, --NHCO lower alkyl(C₁ -C₃), --N--lower alkyl(C₁ -C₃)!₂, --SO₂ NH₂ ; --SO₂ NH lower alkyl (C₁ -C₃) or--SO₂ N lower alkyl (C₁ -C₃)!₂ ;

R₂ is hydrogen, Cl, Br, F, I, --OH, lower alkyl(C₁ -C₃), O-loweralkyl(C₁ -C₃), or R₁ and R₂ taken together are methylenedioxy orethylenedioxy;

R₃ is the moiety: ##STR5## wherein Ar is a moiety selected from thegroup ##STR6## and X is O, S, --NCH₃, or --N--COCH₃ ; R₄ is hydrogen,lower alkyl(C₁ -C₃); --CO-lower alkyl (C₁ -C₃); phenylCO, phenylSO₂ ;tolylSO₂ ; SO₂ lower alkyl (C₁ -C₃); or moieties of the formulae:##STR7## R₅ is hydrogen, --CH₃, --C₂ H₅, Cl, Br, F, --O--CH₃, or --O--C₂H₅ ;

R₆ is selected from (a) moieties of the formula: ##STR8## whereincycloalkyl is defined as C₃ to C₆ cycloalkyl, cyclohexenyl orcyclopentenyl; R_(a) is hydrogen, CH₃, C₂ H₅, moieties of the formulae:##STR9## --(CH₂)₂ O-lower alkyl (C₁ -C₃) or --CH₂ CH₂ OH; q is one ortwo; R_(b) is hydrogen, CH₃ or --C₂ H₅ ;

(b) a moiety of the formula: ##STR10## where R₂ is as hereinbeforedefined; (c) a moiety of the formula: ##STR11## wherein J is R_(a),lower alkyl(C₁ -C₈) branched or unbranched, lower alkenyl(C₂ -C₈)branched or unbranched, O-lower alkyl(C₁ -C₈) branched or unbranched,--O-lower alkenyl(C₂ -C₈) branched or unbranched, tetrahydrofuran,tetrahydrothiophene, or --CH₂ --K wherein K is halogen, --OH,tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:##STR12## wherein D, E, F and G are selected from carbon or nitrogen andwherein the carbon atoms may be optionally substituted with halogen, (C₁-C₃)lower alkyl, hydroxy, --CO-lower alkyl(C₁ -C₃), CHO, (C₁ -C₃)loweralkoxy, --CO₂ -lower alkyl(C₁ -C₃), and R_(a) and R_(b) are ashereinbefore defined;

(d) a moiety selected from those of the formulae: ##STR13## whereinR_(c) is selected from halogen, (C₁ -C₃)lower alkyl, --O-lower alkyl(C₁-C₃) and OH, R_(b) is as hereinbefore defined;

Ar' is a moiety selected from the group ##STR14## R₇ is hydrogen, --CH₃,--C₂ H₅, Cl, Br, F, --OCH₃, --OC₂ H₅, or --CF₃ ;

R₈ and R₉ are independently hydrogen, lower alkyl (C₁ -C₃); O-loweralkyl(C₁ -C₃); S-lower alkyl(C₁ -C₃), --CF₃, --CN, --OH, --SCF₃, --OCF₃,halogen, NO₂, amino or NH lower alkyl(C₁ -C₃);

R₁₀ is halogen, hydrogen or lower alkyl(C₁ -C₃); W' is O, S, NH, N-loweralkyl(C₁ -C₃), NCO-lower alkyl(C₁ -C₃) or NSO₂ -lower alkyl(C₁ -C₃).##STR15## represents: (1) fused phenyl or fused substituted phenyloptionally substituted by one or two substituents selected from (C₁ -C₃)lower alkyl, halogen, amino, (C₁ -C₃) lower alkoxy, or (C₁ -C₃) loweralkylamino; (2) a 5-membered aromatic (unsaturated) heterocyclic ringhaving one heteroatom selected from O, N or S; (3) a 6-membered aromatic(unsaturated) heterocyclic ring having one nitrogen atom; (4) a 5 or6-membered aromatic (unsaturated) heterocyclic ring having two nitrogenatoms; (5) a 5-membered aromatic (unsaturated) heterocyclic ring havingone nitrogen atom together with either one oxygen or one sulfur atom;wherein the 5 or 6-membered heterocyclic rings are optionallysubstituted by (C₁ -C₃) lower alkyl, formyl, (C₁ -C₃)loweralkoxycarbonyl, --CO₂ H; a moiety of the formula: ##STR16## halogen or(C₁ -C₃) lower alkoxy. For example, the fused heterocyclic ring may berepresented by furan, pyrrole, pyrazole, thiophene, thiazole, oxazole,imidazole, pyrimidine or pyridine ring which may be substituted orunsubstituted.

DETAILED DESCRIPTION OF THE INVENTION

Within the group of the compounds defined by Formula I, certainsubgroups of compounds are broadly preferred. Broadly preferred arethose compounds wherein R₃ is a moiety: ##STR17## and Ar is selectedfrom the moiety: ##STR18## wherein R₅, R₆ and R₇ are as hereinbeforedefined.

Especially preferred are compounds wherein R₃ is the moiety: ##STR19##and Ar is selected from the moiety: ##STR20## R₆ is NHCOAr' and Ar' is##STR21## wherein R₈, R₉ and W' are as hereinbefore defined.

Also especially broadly preferred are compounds wherein Y in Formula Iis --(CH₂)_(n) -- and n is zero or one; A-B is ##STR22## and R₄, R₅, R₆,R₇, R₈, R₉ and R₁₀ are as hereinbefore defined; and m is an integer from1-2.

The most broadly preferred of the compounds of Formula I are thosewherein Y is --(CH₂)_(n) -- and n is one; A-B is ##STR23## R₃ is themoiety: ##STR24## Ar is ##STR25## R₆ is ##STR26## and Ar' is a moiety:##STR27## Cycloalkyl and W' are as previously defined and R₈ and R₉ arepreferably ortho CF₃, Cl, OCH₃, CH₃, SCH₃ or OCF₃ substituents or Ar' isa disubstituted derivative wherein R₈ and R₉ are independently Cl, OCH₃,CH₃.

The most highly broadly preferred of the compounds of Formula I arethose wherein Y is --(CH₂)n--, n is zero or one and ##STR28## representsa fused phenyl, substituted phenyl, thiophene, furan, pyrrole orpyridine ring;

A-B is ##STR29## m is one when n is one and m is two when n is zero; R₃is the moiety: ##STR30## wherein Ar is ##STR31## and R₆ is selected fromthe group ##STR32## where Ar' is selected from the group ##STR33## andR_(a), R_(b), R₁, R₂, R₄, R₅, R₆, R₇, R₈, R₉ and W' are as previouslydefined.

Most particularly preferred are compounds of the formulae: ##STR34##wherein m is an integer one or two; R₁ and R₂ are as previously defined;

R₃ is the moiety: ##STR35## wherein Ar is selected from moieties of theformulae: ##STR36## R₆ is ##STR37## wherein cycloalkyl is defined as C₃-C₆ cycloalkyl, cyclohexenyl or cyclopentenyl and wherein Ar' isselected from the moieties: ##STR38## R_(a) is independently selectedfrom hydrogen, CH₃ or --C₂ H₅ ; and R₅, R₇, R₈, R₉, R₁₀ and W' are ashereinbefore defined.

Compounds of this invention may be prepared as shown in Scheme I byreaction of tricyclic derivatives of Formula 3a and 3b with asubstituted or unsubstituted 4-nitrobenzoyl chloride 4 to give theintermediates 5a and 5b. Reduction of the nitro group in intermediates5a and 5b gives the 4-aminobenzoyl derivatives 6a and 6b. The reductionof the nitro group in intermediates 5a and 5b may be carried out undercatalytic reduction conditions (hydrogen-Pd/C; Pd/C- hydrazine-ethanol)or under chemical reduction conditions (SnCl₂ -ethanol; Zn-acetic acid;TiCl₃) and related reduction conditions known in the art for convertinga nitro group to an amino group. The conditions for conversion of thenitro group to the amino group are chosen on the basis of compatibilitywith the preservation of other functional groups in the molecule.

Reaction of compounds of Formula 6a and 6b with aroyl chloride orrelated activated aryl carboxylic acids in solvents such as chloroform,dichloromethane, dioxane, tetrahydrofuran, toluene and the like in thepresence of a tertiary base such as triethylamine anddiisopropylethylamine or pyridine and the like, affords the compounds 8aand 8b which are vasopressin antagonists. ##STR39##

Reaction of tricyclic derivatives of Formula 6a and 6b with either acarbamoyl derivative 9 or a isocyanate derivative 10 gives compounds(Scheme 2) of Formula 11a and 11b which are vasopressin antagonists ofFormula I wherein R₆ is ##STR40## and R_(b) is H, CH₃ or C₂ H₅.##STR41##

Reaction of tricyclic derivatives of Formula 6a and 6b with arylaceticacids, activated as the acid chlorides 12, anhydrides, mixed anhydridesor activated with known activating reagents, gives compounds 13a and 13b(Scheme 3). ##STR42##

The compounds of Formula I wherein Y, A-B, Z, R₁, R₂ and R₃ are asdefined and the aryl of R₃ (--COAr) is ##STR43## may be prepared, asshown in Scheme 4, by reacting an activated ester of theindole-5-carboxylic acids 14 with tricyclic derivatives 3a and 3b. Theindole-5-carboxylic acids 14 may be activated by preparing theanhydride, a mixed anhydride or reacting with diethyl cyanophosphonate,N,N-carbonyldiimidazole or related peptide coupling reagents. As anexample, the derivative 15 may be prepared by the reaction of acid 14and N,N-carbonyldiimidazole in tetrahydrofuran; the solvent is removedand the derivative reacted with 3a or 3b at 100° C. to 120° C. without asolvent. Alternatively, 3a and 3b may be reacted with 15 in a solventsuch as toluene or xylene at reflux temperatures. The activating reagentfor the indole acids 14 is chosen on the basis of its compatibility withthe R₄ group and its reactivity with the tricyclic derivatives 3a and 3bto give the vasopressin antagonists 16a and 16b. ##STR44##

The compounds of Formula I wherein Y, A-B, Z, R₁, R₂ and R₃ are asdefined and the R₃ (--COAr) aryl group is ##STR45## wherein R₆ is##STR46## may be prepared as shown in Scheme 5 by first reacting thederivatives 18a and 18b with sodium hydride or similar reagents to formthe amide anion and then reacting the anion with a dialkoxyphosphorylchloride to give the intermediates 17a and 17b. Reaction of theseintermediates with sodium or lithium azide gives the products 18a and18b. ##STR47##

Alternatively, the products 18a and 18b may be prepared by couplingtetrazole derivatives of the Formula 19 with tricyclic derivatives 3aand 3b (Scheme 6). The tetrazole carboxylic acids are activated forcoupling to the tricyclic compounds 3a and 3b by reaction with peptidecoupling reagents, by conversion to the acid chlorides, anhydrides ormixed anhydrides. ##STR48##

As an alternative method for synthesis of compounds of this invention asdepicted in Formula I wherein Y, A-B, R₁, R₂, and Z are as previouslydefined and R₃ is ##STR49## is the coupling of aryl carboxylic acids 20awith the tricyclic derivatives 3a and 3b as shown in Scheme 7.

The aryl carboxylic acids are activated for coupling by conversion to anacid chloride, bromide or anhydride or by first reacting with anactivating reagent such as N,N-dicyclocarbodiimide, diethylcyanophosphonate and related "peptide type" activating reagents. Themethod of activating the acids 20a for coupling to the tricyclicderivatives 3a and 3b is chosen on the basis of compatibility with othersubstituent groups in the molecule. The method of choice is theconversion of the aryl carboxylic acids 20a to the corresponding aroylchloride. The aryl acid chlorides 50 may be prepared by standardprocedures known in the art, such as reaction with thionyl chloride,oxalyl chloride and the like. The coupling reaction is carried out insolvents such as halogenated hydrocarbons, toluene, xylene,tetrahydrofuran dioxane in the presence of pyridine or tertiary basessuch as triethylamine and the like. Alternatively, the aroyl chlorides,prepared from the aryl carboxylic acids 20, may be reacted withderivatives 3a and 3b in pyridine with or without4-(dimethylamino)pyridine to give derivatives 21a and 21b.

In general, when the aryl carboxylic acids are activated withN,N-carbonyldiimidazole and other "peptide type" activating reagents,higher temperatures are required than when the aroyl chlorides are used.The reaction may be carried out in a higher boiling solvent xylene orwithout a solvent (100° C. to 150° C.). ##STR50##

The starting materials 3a and 3b in Scheme 1 can be made by literaturemethods. For example, intermediate 6,11-dihydro-5H-dibenz b,e!azepinesand substituted derivatives are prepared according to literatureprocedures: L. H. Werner, et al., J. Med. Chem., 8, 74-80 (1965); A. W.H. Wardrop et al., J. Chem. Soc. Perkins Trans I, 1279-1285 (1976).

Substituted 5,11-dihydrodibenz b,e!azepin-6-one are prepared byliterature procedures: J. Schmutz et al., Helv. Chim. Acta., 48, 336(1965); and reduced to substituted 6,11-dihydro-5H-dibenz b,e!azepineswith lithium aluminum hydride, diborane, diborane-dimethylsulfide andagents known to reduce an amide carbonyl to a methylene group.Intermediate 10,11-dihydrodibenz b, f! 1,4!thiazepines are prepared byliterature procedures--for example, see K. Brewster et al., J. Chem.Soc. Perkin I, 1286 (1976). Reduction of either dibenz b,f!1,4!oxazepines A. W. H. Wardrop et al., J. Chem. Soc. Perkin Trans. I,1279 (1976)! and dibenz b,f! 1,41!oxazepin-11(10H)-ones and dibenz- b,f!1,4!thiazepin-11(10H)-ones--J. Schmutz et al., Helv. Chim. Acta, 48, 336(1965); may be carried out with lithium aluminum hydride in inertsolvents such as dioxane and the like. The tricyclic6,7-dihydro-5H-dibenz b,d!azepine intermediates of Formula 30 may beprepared by the literature procedures: T. Ohta et al., TetrahedronLett., 26, 5811 (1985); Wiesner et al., J. Amer. Chem. Soc., 77, 675(1955); or derivatives may be prepared by coupling proceduresillustrated in Scheme 8. The reduction of nitro compounds of structuretype 31 followed by ring closure, affords lactams 32 which are reducedto give tricyclic azepines of Formula 33.

5,11-Dihydro-6H-pyrido 3,2-c! 1!benzazepines are prepared by literatureprocedures--J. Firl et. al., Liebius Ann. Chem. 469, (1989). Tricyclic1,2,3,4-tetrahydropyrazolo 4,3-c! 1!benzazepines are synthesized asdescribed in the literature--G. Palazpino et. al., J. MeterocyclicChem., 26, 71 (1989). ##STR51##

Tricyclic intermediates 42 for the synthesis of selected vasopressinantagonists of this invention wherein Y in Formula I is --CH₂ -- and mis one, may be prepared as shown in Scheme 9. Suitable 1-nitro-2-chloroor 1-nitro-2-bromo heterocycles 35 undergo halogen exchange when reactedwith an alkyllithium reagent such as t-butyllithium, s-butyllithium orn-butyllithium to give intermediates 37 which react with anhydrides ofFormula 38. R₁₂ is tert-butyl, secondary butyl, n-butyl,2,6-dimethylpiperidine or a hindered non-nucleophilic dialkylamine. Thenitro products 39 are reduced with hydrogen and a suitable catalyst orchemically reduced (Zn-acetic acid, TiCl₃ etc.) to the aminointermediates 40. Ring closure to the cyclic lactams 41 is convenientlycarried out by heating in xylene or an inert solvent at 100° C. to 200°C. The cyclic lactams of structure type 41 are readily reduced bydiborane in tetrahydrofuran, diborane-dimethylsulfide in tetrahydrofuranor lithium aluminum hydride in a suitable solvent such as dioxane togive the tricyclic compounds 42. ##STR52##

Alternatively, as shown in Scheme 10, some of the tricyclic derivativesof structural type 42 may be prepared by "palladium" type coupling or"copper" induced coupling of halogenated derivatives 43 to givetricyclic lactams 44. Reduction of the lactam carbonyl group gives theintermediates 42. Coupling of halogen derivatives 45 to effect ringclosure with activated copper or "palladium" type reagents which inducearyl coupling gives lactams 46. Diborane reduction of lactams 46 givesderivatives 47. Ullmann cross-couplings of halogenated heterocycles and2-bromo-nitrobenzenes and related cross-couplings by low valentpalladium species such as Pd(PPh₃)₄ ! and PdCl₂ (PPh₃)₂ are knownsynthetic procedures; N. Shimizu et al., Tetrahedron Lett. 34, 3421(1993) and references therein; N. M. Ali etal., Tetrahedron, 37, 8117(1992) and references therein; J. Stavenuiter et al., Heterocycles, 26,2711 (1987) and references therein. ##STR53##

Tetrahydro-1H-1-benzazepin-5-ones 51 and thetetrahydro-1H-1-benzazepin-2,5-diones 52 are useful compounds for thesynthesis of intermediate tricyclic heterocyclic structures 53 and 54(Scheme 11). The tetrahydrobenzazepin-5-ones 51 and 52 may be formylatedto give hydroxymethylene derivatives or reacted with either theVilsmeier reagent or the N,N-dimethylformamide dimethyl acetal to givethe dimethylaminomethylene derivatives. The construction of heterocyclicrings from α-hydroxymethyleneketones by reactions with hydrazineN-methylhydrazine, hydroxylamine or formamidine to give pyrazoles,N-methylpyrazoles, oxazoles or pyrimidines respectively, is a standardliterature procedure. See Vilsmeier formylation--Tetrahedron, 49,4015-4034 (1993) and references therein and ring formations--J.Heterocyclic Chem., 29, 1214 (1992) and references therein.

Substituted and unsubstituted tetrahydrobenzazepin-2-ones are knowncompounds which are prepared by reaction of α-tetralones with sodiumazide under acidic conditions. J. Chem. Soc. 456 (1937); Tetrahedron 49,1807 (1993)! (Schmidt reaction). Reduction oftetrahydro-1H-benzazepin-2-ones gives the tetrahydro-1H-benzazepines 48which on acylation gives compounds 49. Oxidation of N-acyltetrahydro-1H-benzapines of type 49 to give the 5-one derivatives is aknown oxidative procedure; R. L. Augustine and W. G. Pierson, J. Org.Chem., 34, 1070 (1969).

The synthesis of 3,4-dihydro-1H-1-benzazepine-2,5-diones (52:R₁₅ =H) hasbeen reported as well as the conversion of3,4-dihydro-1H-1-benzazepine-2,5-diones to 4-(dimethylamino)methylene!-3,4-dihydro-1H-1-benzazepine-2,5-diones withN,N-dimethylformamide, dimethylacetal: W. -Y. Chen and N. W. Gilman, J.Heterocyclic Chem., 20, 663 (1983)!. The preceding reference describesthe synthesis of 2-methyl-5,7-dihydropyrimido 5,4-d!1!benzazepin-6(6M)-ones which may be reduced to remove the lactamcarbonyl group to give tricyclic derivatives of structural type 54wherein Z is a pyrimidine ring. ##STR54##

The synthesis of compounds of Formula I wherein R₃ is ##STR55## the Argroup is ##STR56## R₆ is ##STR57## and where Ar' is as previouslydefined is carried out according to Scheme 12. The tricyclic compounds3a and 3b are reacted with mono-methyl terephythalyl chloride 55(prepared from mono-methyl terephthalate and thionyl chloride) in thepresence of a tertiary base such as triethylamine in solvents such asdichloromethane, tetrahydrofuran, dioxane, toluene and the like to givederivatives 56a and 56b. These ester intermediates (56a and 56b) arehydrolyzed with two to ten equivalents of an alkaline hydroxide such aspotassium or sodium hydroxide in aqueous methanol or ethanol to give thecorresponding acids after acidification and workup. The free acids areconverted to the acid chlorides with thionyl chloride and these acidchloride intermediates, 57a and 57b, reacted with aminoaryl derivativesof formula: ##STR58## wherein Ar' is as previously defined to givecompounds 59a and 59b. ##STR59##

As described in reaction Scheme 1, the following specific tricyclic ringsystems of the generic formula 3a and 3b are illustrated to show one ofthe synthetic methods for the synthesis of the compounds of thisinvention. These derivatives 60, 63, 66, 69, 72, 75, 78, 81, 84, 87, 90,and 93 when subjected to the reaction conditions in Scheme 1 which isthe acylation of the tricyclic compounds (R₁₆ =H) with 4-nitrobenzoylchloride or a substituted 4-nitrobenzoyl chloride in the presence of atrialkylamine such as triethylamine in solvents such as chloroform,dichloromethane, dioxane, tetrahydrofuran, toluene and the like give theintermediates 61, 64, 67, 70, 75, 76, 79, 82, 85, 88, 91, 94. These4-nitro-benzoyl and substituted 4-nitro-benzoyl derivatives are reducedwith hydrogen in the presence of a catalyst such as Pd/C in solventssuch as ethanol, ethanol-ethyl acetate, acetic acid orN,N-dimethylformamide to give the 4-aminobenzyl or substituted4-aminobenzoyl derivatives 62, 65, 68, 72, 74, 77, 80, 83, 86, 89, 92,95. Alternatively, the 4-nitrobenzoyl and substituted 4-nitrobenzoylderivatives 61, 64, 67, 70, 73, 76, 79, 82, 85, 88, 91, 94 are reducedwith Pd/C and hydrazine in refluxing ethanol.

The 4-aminobenzoyl and substituted 4-aminobenzoyl derivatives 62, 65,68, 71, 74, 77, 80, 83, 86, 89, 92, 95 are reacted with acid chloridesof the formula:

Ar'COCl, ##STR60## cycloalkyl(CH₂)_(n) COCl, Ar'CH₂ COCl, to giveproducts as shown in Scheme 1 wherein R₆ is as defined. ##STR61##

As described in Scheme 2, the tricyclic 4-aminobenzoyl or substituted4-aminobenzoyl derivatives 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92,and 95 are reacted with carbamoyl derivatives ##STR62## orarylisocyanates

    Ar'-N=C=O

to give specific derivatives wherein R₆ is ##STR63## and R_(b) isindependently selected from H, CH₃ or --C₂ H₅.

As described in Scheme 7, the tricyclic derivatives 60, 63, 66, 69, 72,75, 78, 81, 84, 87, 90, and 93 are reacted in one step with a previouslysynthesized ArCOCl compound wherein Ar is as previously defined. Forexample, reaction of the specific tricyclic derivatives 60, 63, 66, 69,72, 75, 78, 81, 84, 87, 92, 93 with aroyl chlorides of the followingstructural types: ##STR64## gives in one step derivatives of thesedelineated tricyclic compounds wherein the Ar group of the moiety:##STR65## in formula I is ##STR66## and R₆ is ##STR67## whereincycloalkyl, R_(a), R_(b), R₁, R₂, R₅, R₇ and Ar' are as hereinbeforedescribed.

Among the more preferred compounds of this invention are those selectedfrom Formula I: ##STR68## wherein; Y is a bond;

A-B is ##STR69## R₁ is H, halogen (chlorine, fluorine, bromine, iodine),OH, --S-lower alkyl (C₁ -C₃) , --SH, --SO lower alkyl (C₁ -C₃), --SO₂lower alkyl (C₁ -C₃), --CO lower alkyl (C₁ -C₃), --CF₃, lower alkyl (C₁-C₃), --O lower alkyl (C₁ -C₃), --NO₂, --NH₂, --NHCO lower alkyl (C₁-C₃), --N-- lower alkyl (C₁ -C₃)!₂, SO₂ NH₂, --SO₂ NH lower alkyl (C₁-C₃), or --SO₂ N lower alkyl (C₁ -C₃)!₂ ;

R₂ is H, Cl, Br, I, F, --OH, lower alkyl (C₁ -C₃), --O lower alkyl (C₁-C₃); or

R₁ and R₂ taken together are methylenedioxy or ethylenedioxy;

R₃ is the moiety ##STR70## wherein Ar is a moiety selected from thegroup ##STR71## and X is selected from O, S, --NCH₃, or --N--COCH₃ ; R₄is selected from H, lower alkyl (C₁ -C₃), --CO-lower alkyl (C₁ -C₃), SO₂lower alkyl (C₁ -C₃), and the moieties of the formulae: ##STR72## R₅ isH, --CH₃, --C₂ H₅, Cl, Br, F, --O--CH₃, or --O--C₂ H₅ ;

R₆ is selected from:

(a) moieties of the formula: ##STR73## wherein cycloalkyl is defined asC₃ -C₆ cycloalkyl, cyclohexenyl or cyclopentenyl;

R₂ is as hereinbefore defined;

n is 0-2;

R₇ is H, --CH₃, --CH₂ H₅, Cl, Br, F, --OCH₃, --OC₂ H₅, or --CF₃ ;

R_(a) is hydrogen, CH₃, C₂ H₅, moieties of the formulae: ##STR74##--(CH₂)₂ --O-lower alkyl (C₁ -C₃) or --CH₂ CH₂ OH;

q is one or two;

R_(b) is hydrogen, --CH₃ or --C₂ H₅ ;

Ar' is selected from the group: ##STR75## wherein R₄, R₅ are ashereinbefore defined;

R₈ and R₉ are independently hydrogen, lower alkyl (C₁ -C₃), O-loweralkyl (C₁ -C₃), S-lower alkyl (C₁ -C₃), --CF₃, --CN, --OH, --SCF₃,--OCF₃, halogen, NO₂, amino, or --NH-lower alkyl (C₁ -C₃);

R₁₀ is selected from halogen, hydrogen, or lower alkyl (C₁ -C₃);

W' is selected from O, S, NH, N-lower alkyl (C₁ -C₃), --NCO-lower alkyl(C₁ -C₃), or NSO₂ -lower alkyl (C₁ -C₃);

and

(b) a moiety of the formula: ##STR76## where R₂ is as hereinbeforedefined;

(c) a moiety of the formula: ##STR77## wherein J is R_(a), lower alkyl(C₁ -C₈) branched or unbranched, lower alkenyl (C₂ -C₈) branched orunbranched, --O-lower alkyl (C₁ -C₈) branched or unbranched, --O-loweralkenyl (C₂ -C₈) branched or unbranched, tetrahydrofuran,tetrahydrothiophene, or --CH₂ --K wherein K is halogen, --OH,tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:##STR78## wherein D, E, F and G are selected from carbon or nitrogen andwherein the carbon atoms may be optionally substituted with halogen, (C₁-C₃)lower alkyl, hydroxy, --CO-lower alkyl (C₁ -C₃), CHO, (C₁ -C₃)loweralkoxy, or --CO₂ -lower alkyl (C₁ -C₃), and R_(a) and R_(b) are ashereinbefore defined;

(d) a moiety selected from those of the formulae: ##STR79## whereinR_(c) is selected from halogen, (C₁ -C₃) lower alkyl, --O-lower alkyl(C₁ -C₃) or OH;

R_(b) is as hereinbefore defined;

q is 1 or 2;

wherein Ar' is selected from the group: ##STR80## R₇ is hydrogen, --CH₃,--C₂ H₅, Cl, Br, F, --OCH₃, --OC₂ H₅, or --CF₃ ;

R₈ and R₉ are independently hydrogen, lower alkyl (C₁ -C₃), O-loweralkyl (C₁ -C₃), S-lower alkyl (C₁ -C₃), --CF₃, --CN, --OH, --SCF₃,--OCF₃, halogen, NO₂, amino, or --NH-lower alkyl (C₁ -C₃);

R₁₀ is selected from the group of halogen, hydrogen, or lower alkyl (C₁-C₃);

W' is selected from O, S, NH, N-lower alkyl (C₁ -C₃), --NCO-lower alkyl(C₁ -C₃), or NSO₂ -lower alkyl (C₁ -C₃);

the moiety ##STR81## represents a fused thiophene ring or fusedsubstituted thiophene ring optionally substituted by one or twosubstituents selected from (C₁ -C₃) lower alkyl, halogen, formyl, (C₁-C₃) lower alkoxy, (C₁ -C₃) lower alkoxycarbonyl, --CO₂ H, a moiety ofthe formula: ##STR82## or a pharmaceutically acceptable salt, ester orprodrug thereof.

Within the group above are the following preferred sub-groups 1 and 2 ofcompounds:

1. wherein R³ is the moiety ##STR83## wherein Ar is a moiety selectedfrom the group ##STR84## R₆ is selected from the group ##STR85## or--CH₂ COAr'; wherein

n is 0-2;

Ar' is ##STR86## W' is O or S; A-B, R_(a), R_(b), R₁, R₂, R₄, R₅, R₇,R₈, R₉, and cycloalkyl are as defined in claim 1;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

2. compounds of the formula: ##STR87## wherein; Y is a bond;

A-B is ##STR88## R₁ is H, halogen (Cl, F, Br, I), OH, --S-lower alkyl(C₁ -C₃), --SH, --SO lower alkyl (C₁ -C₃), --SO₂ lower alkyl (C₁ -C₃),--CO lower alkyl (C₁ -C₃), --CF₃, lower alkyl (C₁ -C₃), --O lower alkyl(C₁ -C₃), --NO₂, --NH₂, --NHCO lower alkyl (C₁ -C₃), --N- lower alkyl(C₁ -C₃)!₂, SO₂ NH₂, SO₂ NH lower alkyl (C₁ -C₃), or --SO₂ N lower alkyl(C₁ -C₃)!² ;

R₂ is selected from H, Cl, Br, I, F, --OH, lower alkyl (C₁ -C₃), or --Olower alkyl (C₁ -C₃); or

R₁ and R₂ taken together are methylenedioxy or ethylenedioxy;

R₃ is the moiety ##STR89## wherein Ar is a moiety selected from thegroup ##STR90## R₅ is H, --CH₃, --C₂ H₅, Cl, Br, F, --O--CH₃, or --O--C₂H₅ ;

R₆ is selected from: ##STR91## wherein cycloalkyl is defined as C₃ -C₆cycloalkyl, cyclohexenyl or cyclopentenyl;

n is 0-2;

and wherein Ar' is selected from the moieties: ##STR92## wherein R_(a)and R_(b) are independently selected from H, --CH₃, or --C₂ H₅ ;

R₇ is H, --CH₃, --C₂ H₅, Cl, Br, F, --O--CH₃, --O--C₂ H₅ or --CF₃ ;

R₈ and R₉ are independently selected from hydrogen, lower alkyl (C₁-C₃), O-lower alkyl (C₁ -C₃), S-lower alkyl (C₁ -C₃), --CF₃, --CN, --OH,--SCF₃, --OCF₃, halogen, NO₂, amino, or --NH-lower alkyl (C₁ -C₃);

W' is selected from O, S, NH, N-lower alkyl (C₁ -C₃), --NCO-lower alkyl(C₁ -C₃), or

NSO₂ -lower alkyl (C₁ -C₃);

the moiety ##STR93## represents a fused thiophene ring or fusedsubstituted thiophene ring optionally substituted by one or twosubstituents selected from (C₁ -C₃) lower alkyl, halogen, formyl, (C₁-C₃) lower alkoxy, (C₁ -C₃) lower alkoxycarbonyl, --CO₂ H, a moiety ofthe formula: ##STR94## or a pharmaceutically acceptable salt, ester orprodrug thereof.

Among the more preferred compounds of this invention are those selectedfrom:

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)phenyl!-2-methyl-3-fluorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)phenyl!-2-methylbenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)phenyl!-2-methyl-5-fluorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d! 1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-fluorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methylbenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methyl-5-fluorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-chloro-5-fluorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)-3-chloro-phenyl!-2-(methylthio)-5-fluorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)phenyl!-2-chloro-5-fluorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-chlorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-chlorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methoxy-5-fluorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-chloro-4-fluorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)-3-methyl-phenyl!-2-methyl-3-fluorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)-3-methoxy-phenyl!-2-methylbenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)-3-methyl-phenyl!-2-methyl-5-fluorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-2-methyl-3-fluorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-fluorophenyl!-2-methylbenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d! 1!benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-2-methyl-5-fluorobenzamide.

N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-methylphenyl!-2-chloro-5-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-chlorophenyl!-2-methyl-5-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-chlorophenyl!-2-chloro-5-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-chlorophenyl!-2,5-dichlorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-phenyl!-2-methyl-5-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-phenyl!-2-methyl-3-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-methylphenyl!-2-methyl-5-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-methylphenyl!-2-methyl-3-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-methylphenyl!-2-chloro-5-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-methylphenyl!-2,5-dichlorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-methoxyphenyl!-2-methyl-5-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-methoxyphenyl!-2-methyl-3-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3,6-dimethylphenyl!-2-methyl-5-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3,6-dimethylphenyl!-2-methyl-3-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-chlorophenyl!-2-chloro-4-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-chlorophenyl!-2-chloro-6-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-phenyl!-2-methoxy-5-fluorobenzamide.

N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-phenyl!-2-(methylthio)-5-fluorobenzamide.

The subject compounds of the present invention are tested for biologicalactivity as follows:

Binding Assay to Rat Hepatic V₁ Receptors

Rat liver plasma membranes expressing the vasopressin V₁ receptorsubtypes are isolated by sucrose density gradient according to themethod described by Lesko et al., (1973). These membranes are quicklysuspended in 50.0 mM Tris.HCl buffer, pH 7.4, containing 0.2% bovineserum albumin (BSA) and 0.1 mM phenylmethylsulfonylfluoride (PMSF) andkept frozen at -70° C. until used in subsequent binding experiments. Forbinding experiments, the following is added to the wells of a ninety-sixwell format microtiter plate: 100 μl of 100.0 mM Tris.HCl buffercontaining 10.0 mM MgCl₂, 0.2% heat inactivated BSA and a mixture ofprotease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %;1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mMPMSF, 20.0 μl of phenylalanyl-3,4,5,-³ H! vasopressin (S.A. 45.1Ci/mmole) at 0.8 nM, and the reaction initiated by the addition of 80 μlof tissue membranes containing 20 μg of tissue protein. The plates arekept undisturbed on the bench top at room temperature for 120 min. toreach equilibrium. Non-specific samples are assayed in the presence of0.1 μM of the unlabeled antagonist phenylalanylvasopressin, added in20.0 μl volume.

For test compounds, these are solubilized in 50% dimethylsulfoxide(DMSO) and added in 20.0 μl volume to a final incubation volume of 200μl. Upon completion of binding, the content of each well is filteredoff, using a Brandel® cell Harvester (Gaithersburg, Md.). Theradioactivity trapped on the filter disk by the ligand-receptor complexis assessed by liquid scintillation counting in a Packard LS Counter,with an efficiency of 65% for tritium. The data are analyzed for IC₅₀values by the LUNDON-2 program for competition (LUNDON SOFTWARE, OH) anddisplayed in Table I.

Binding Assay to Rat Kidney Medullary V₂ Receptors

Medullary tissues from rat kidneys are dissected out, cut into smallpieces and soaked in a 0.154 mM sodium chloride solution containing 1.0mM EDTA with many changes of the liquid phase, until the solution isclear of blood. The tissue is homogenized in a 0.25M sucrose solutioncontaining 1.0 mM EDTA and 0.1 mM PMSF using a Potter-Elvehjemhomogenizer with a teflon pestle. The homogenate is filtered throughseveral layers (4 layers) of cheese cloth. The filtrate is rehomogenizedusing a dounce homogenizer, with a tight fitting pestle. The finalhomogenate is centrifuged at 1500×g for 15 min. The nuclear pellet isdiscarded and the supernatant fluid recentrifuged at 40,000×g for 30min. The resulting pellet formed contains a dark inner part with theexterior, slightly pink. The pink outer part is suspended in a smallamount of 50.0 mM Tris.HCl buffer, pH 7.4. The protein content isdetermined by the Lowry's method (Lowry et al., J. Biol. Chem., 1953).The membrane suspension is stored at -70° C., in 50.0 mM Tris.HCl,containing 0.2% inactivated BSA and 0.1 mM PMSF in aliquots of 1.0 mlcontaining 10.0 mg protein per ml of suspension until use in subsequentbinding experiments.

For binding experiments, the following is added in μl volume to wells ofa 96 well format of a microtiter plate: 100.0 μl of 100.0mM Tris.HClbuffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl₂ and a mixtureof protease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %;1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mMPMSF, 20.0 μl of ³ H! Arginine⁸, vasopressin (S.A. 75.0 Ci/mmole) at 0.8nM and the reaction initiated by the addition of 80.0 μl of tissuemembranes (200.0 μg tissue protein). The plates are left undisturbed onthe bench top for 120 min to reach equilibrium. Non-specific binding isassessed in the presence of 1.0 μM of unlabeled ligand, added in 20 μlvolume. For test compounds, these are solubilized in 50%dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a finalincubation volume of 200 μl. Upon completion of binding, the content ofeach well is filtered off, using a Brandel® cell Harvester(Gaithersburg, Md.). The radioactivity trapped on the filter disk by theligand-receptor complex is assessed by liquid scintillation counting ina Packard LS Counter, with an efficiency of 65% for tritium. The dataare analyzed for IC₅₀ values by the LUNDON-2 program for competition(LUNDON SOFTWARE, OH) and displayed in Table I.

Radioligand Binding Experiments with Human Platelet Membranes

(a) platelet Membrane Preparation:

Frozen platelet rich plasma (PRP), received from the Hudson Valley BloodServices, are thawed to room temperature. (Platelet Source: HudsonValley Blood Services, Westchester Medical Center, Valhalla, N.Y.). Thetubes containing the PRP are centrifuged at 16,000×g for 10 min. at 4°C. and the supernatant fluid discarded. The platelets resuspended in anequal volume of 50.0 mM Tris.HCl, pH 7.5 containing 120 mM MaCl and 20.0mM EDTA. The suspension is recentrifuged at 16,000×g for 10 min. Thiswashing step is repeated one more time. The wash discarded and the lysedpellets homogenized in low ionic strength buffer of Tris.HCl, 5.0 mM, pH7.5 containing 5.0 mM EDTA. The homogenate is centrifuged at 39,000×gfor 10 min. The resulting pellet is resuspended in Tris.HCl buffer, 70.0mM, pH 7.5 and recentrifuged at 39,000×g for 10 min. The final pellet isresuspended in 50.0 mM Tris.HCl buffer pH 7.4 containing 120 mM NaCl and5.0 mM KCl to give 1.0-2.0 mg protein per ml of suspension.

(b) Binding to Vasopressin V₁ receptor subtype in Human

Platelet Membranes:

In wells of a 96 well format microtiter plate, add 100 μl of 50.0 mMTris.HCl buffer containing 0.2% BSA and a mixture of protease inhibitors(aprotinin, leupeptin etc.). Then add 20 μl of ³ H!Ligand (Manning orArg⁸ Vasopressin), to give final concentrations ranging from 0.01 to10.0 nM. Initiate the binding by adding 80.0 μl of platelet suspension(approx. 100 μg protein). Mix all reagents by pipetting the mixture upand down a few times. Non specific binding is measured in the presenceof 1.0 μM of unlabeled ligand (Manning or Arg⁸ Vasopressin). Let themixture stand undisturbed at room temperature for ninety (90) min. Uponthis time, rapidly filter off the incubate under vacuum suction overGF/B filters, using a Brandel Harvester. The radioactivity caught on thefilter disks is determined by the addition of liquid scintillant andcounting in a liquid scintillator.

Binding to Membranes of Mouse Fibroblast Cell Line (LV-2) Transfectedwith the cDNA Expressing the Human V₂ Vasopressin Receptor

(a) Membrane Preparation

Flasks of 175 ml capacity, containing attached cells grown toconfluence, are cleared of culture medium by aspiration. The flaskscontaining the attached cells are rinsed with 2×5 ml of phosphatebuffered saline (PBS) and the liquid aspirated off each time. Finally, 5ml of an enzyme free dissociation Hank's based solution (SpecialtyMedia, Inc., Lafayette, N.J.) is added and the flasks are leftundisturbed for 2 min. The content of all flasks is poured into acentrifuge tube and the cells pelleted at 300×g for 15 min. The Hank'sbased solution is aspirated off and the cells homogenized with apolytron at setting #6 for 10 sec in 10.0 mM Tris.HCl buffer, pH 7.4containing 0.25M sucrose and 1.0 mM EDTA. The homogenate is centrifugedat 1500×g for 10 min to remove ghost membranes. The supernatant fluid iscentrifuged at 100,000×g for 60 min to pellet the receptor protein. Uponcompletion, the pellet is resuspended in a small volume of 50.0 mMTris.HCl buffer, pH 7.4. The protein content is determined by the Lowrymethod and the receptor membranes are suspended in 50.0 mM Tris.HClbuffer containing 0.1 mM phenylmethylsulfonylfluoride (PMSF) and 0.2%bovine serum albumin (BSA) to give 2.5 mg receptor protein per ml ofsuspension.

(b) Receptor Binding

For binding experiments, the following is added in μl volume to wells ofa 96 well format of a microtiter plate: 100.0 μl of 100.0 mM Tris.HClbuffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl₂ and a mixtureof protease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %;1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mMPMSF., 20.0 μl of ³ H! Arginine⁸, vasopressin (S.A. 75.0 Ci/mmole) at0.8 nM and the reaction initiated by the addition of 80.0 μl of tissuemembranes (200.0 μg tissue protein). The plates are left undisturbed onthe bench top for 120 min to reach equilibrium. Non specific binding isassessed in the presence of 1.0 μM of unlabeled ligand, added in 20 μlvolume. For test compounds, these are solubilized in 50%dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a finalincubation volume of 200 μl. Upon completion of binding, the content ofeach well is filtered off, using a Brandel® cell Harvester(Gaithersburg, Md.). The radioactivity trapped on the filter disk by theligand-receptor complex is assessed by liquid scintillation counting ina Packard LS Counter, with an efficiency of 65% for tritium. The dataare analyzed for IC₅₀ values by the LUNDON-2 program for competition(LUNDON SOFTWARE, OH) and the data is displayed in Table I.

                                      TABLE I                                     __________________________________________________________________________    Binding Assay to Rat Hepatic V.sub.1 Receptors and Rat Kidney                 Medullary V.sub.2 Receptors or *Binding to V.sub.1 Receptor Subtype in        Human Platelet and **Binding to Membranes of Mouse                            Fibroblast Cell Line (LV-2) Transfected with the cDNA                         Expressing the Human V.sub.2 Receptor                                                                            V.sub.1 V.sub.2                            Ex. No.                                                                           Structure                      IC.sub.50 μM                                                                       IC.sub.50 μM                    __________________________________________________________________________         ##STR95##                     2.5     0.86                               2                                                                                  ##STR96##                     0.15    0.068                              3                                                                                  ##STR97##                     0.17    0.42                               4                                                                                  ##STR98##                     1.5     1.7                                5                                                                                  ##STR99##                     0.056   0.029                              6                                                                                  ##STR100##                    60% (50 μM)                                                                        80% (50 μM)                     7                                                                                  ##STR101##                    0.63    0.077                              8                                                                                  ##STR102##                    2.8     1.5                                9                                                                                  ##STR103##                    1.1     0.28                               10                                                                                 ##STR104##                    0.17    0.064                              11                                                                                 ##STR105##                    0.16    0.033                              12                                                                                 ##STR106##                    0.39    0.18                               13                                                                                 ##STR107##                    0.34    0.30                               14                                                                                 ##STR108##                    0.057   0.066                              16                                                                                 ##STR109##                    0.053   0.065                              17                                                                                 ##STR110##                    65% (50 μM)                                                                        52% (50 μM)                     18                                                                                 ##STR111##                    0.084   0.52                               19                                                                                 ##STR112##                    1.3     1.2                                20                                                                                 ##STR113##                    17% (10 μM)                                                                        48% (10 μM)                     21                                                                                 ##STR114##                    0.28    0.44                               22                                                                                 ##STR115##                    0.32    0.14                               23                                                                                 ##STR116##                    19% (50 μM)                                                                        47% (50 μM)                     24                                                                                 ##STR117##                    0.17    0.41                               25                                                                                 ##STR118##                    0.052   0.56                               61                                                                                 ##STR119##                    0.052   0.068                              62                                                                                 ##STR120##                    0.404   0.858                              92                                                                                 ##STR121##                    0.098   0.025                              119                                                                                ##STR122##                    0.039   1.1                                121                                                                                ##STR123##                    72% (1 μM)                                                                         80% (1 μM)                      122                                                                                ##STR124##                    *95% (10 μM)                                                                       *92% (10 μM)                    123                                                                                ##STR125##                    0.043   0.19                               124                                                                                ##STR126##                    1.2     0.21                               136                                                                                ##STR127##                    0.016   0.027                              137                                                                                ##STR128##                    0.076   0.064                              138                                                                                ##STR129##                    0.046   0.051                              167                                                                                ##STR130##                    0.51    0.43                               165                                                                                ##STR131##                    0.49    0.37                               166                                                                                ##STR132##                    0.083   0.245                              249                                                                                ##STR133##                    61% (10 μM)                                                                        88% (10 μM)                     250                                                                                ##STR134##                    62% (10 μM)                                                                        77% (10 μM)                     251                                                                                ##STR135##                    1.5     0.14                               252                                                                                ##STR136##                    0.26    0.26                               253                                                                                ##STR137##                    0.31    0.19                               254                                                                                ##STR138##                    0.10    0.037                              255                                                                                ##STR139##                    0.027   0.039                              256                                                                                ##STR140##                    0.10    0.054                              257                                                                                ##STR141##                    *0.016  **0.020                            258                                                                                ##STR142##                    75% (10 μM)                                                                        87% (10 μM)                     259                                                                                ##STR143##                    4.0     13% (10 μM)                     260                                                                                ##STR144##                    0.12    0.065                              261                                                                                ##STR145##                    *0.021  **0.016                            262                                                                                ##STR146##                    *0.62   **0.25                             263                                                                                ##STR147##                    *0.43   **0.047                            264                                                                                ##STR148##                    *0.98   **0.028                            267                                                                                ##STR149##                    0.026   0.082                              268                                                                                ##STR150##                    0.019   0.042                              345                                                                                ##STR151##                    99% (10 μM)                                                                        81% (10 μM)                     379                                                                                ##STR152##                    0.25    0.053                              416                                                                                ##STR153##                    34.5    1.1                                448                                                                                ##STR154##                    0.073   0.19                               449                                                                                ##STR155##                    0.36    0.25                               453                                                                                ##STR156##                    *14% (10 μM)                                                                       26% (10 μM)                     456                                                                                ##STR157##                    *0.036  **0.009                            457                                                                                ##STR158##                    *0.039  **0.012                            458                                                                                ##STR159##                    *0.0018 **0.00071                          454                                                                                ##STR160##                    64% (10 μM)                                                                        33% (10 μM)                     454                                                                                ##STR161##                    64% (10 μM)                                                                        37% (10 μM)                     451                                                                                ##STR162##                    *35% (1 μM)                                                                        **69% (1 μM)                    450                                                                                ##STR163##                    87% (10 μM)                                                                        29% (10 μM)                     452                                                                                ##STR164##                    *0.47   **0.01                             455                                                                                ##STR165##                    *0.25   **0.10                             534                                                                                ##STR166##                    *0.09   **0.073                            __________________________________________________________________________

Vasopressin V₂ Antagonist Activity in Conscious Hydrated Rats

Conscious hydrated rats are treated with compounds under study from 0.1to 100 mg/kg orally or vehicle. Two to four rats are used for eachcompound. One hour later, arginine vasopressin (AVP, antidiuretichormore, ADH) dissolved in peanut oil is administered at 0.4 μg/kgintraperitoneally. Two rats in each test would not receive argininevasopressin but only the vehicle (peanut oil) to serve as water-loadingcontrol. Twenty minutes later each rat is given 30 mL/kg of deionizedwater orally by gavage and is placed individually in a metabolic cageequipped with a funnel and a graduated glass cylinder to collect urinefor four hours. Urine volume is measured and osmolality analyzed by useof a Fiske One-Ten osmometer (Fiske Assoc., Norwood, Mass., USA).Urinary sodium, potassium, and chloride are analyzed by use ofion-specific electrodes in a Beckman E3 (Electrolyte 3) Analyzer. In thefollowing results, decreased urine volume and decreased osmolalityrelative to AVP-control indicates activity. The results are displayed inTable II.

                  TABLE II                                                        ______________________________________                                        Diuretic Effect of CL Compounds (V.sub.2 Antagonism)                          in Normal Sprague-Dawley Rats                                                            Dose            Urine Volume                                                                           Osmolality                                Ex. No.    (mg/kg) N       (ml/4hrs.)                                                                             (mOsm/kg)                                 ______________________________________                                        Water-Load         78      13.3 ± 0.3                                                                           229 ± 6                               Control                                                                       Water-Load                                                                    Control + DMSO                                                                (10%)              6        12.1 ± 1                                                                            497 ± 53                              (20%)              4        12.4 ± 0.8                                                                          361 ± 30                              AVP-Control        76        2 ± 0.2                                                                           1226 ± 58                               2         30      6       18.9 ± 1.7                                                                           401 ± 49                                         10      6       15.2 ± 2.4                                                                           408 ± 34                                          3      6        2.9 ± 0.5                                                                          1235 ± 162                              5         10      2        2       1137                                       10        10      2        7.1     1023                                       11        30      4        9.7 ± 0.6                                                                          1114 ± 55                               14        30      2       13.1      739                                       16        30      2        7.2     1257                                       22        30      2       10.2      738                                       61        10      2        9.3      975                                       62        10      2        7.7     1034                                       92        10      2       13.5      679                                      121        10      2        5       1064                                      123        10      2        5.8     1125                                      124        10      2        5.5     1172                                      136        30      2       19        306                                      137        30      2       15.8      358                                      138        30      2       13.8      380                                      167        30      2        2       1544                                      250        30      2        6.5     1378                                      251        10      2        7.5      835                                      252        10      2        7.5      790                                      253        10      2        6        837                                      255        30      2        2.3     1456                                      257        10      2       11.8      434                                      259        10      2        6       1080                                      260        10      4       13.8 ± 2.1                                                                           498 ± 25                              261        10      2        3.8     1337                                      262        10      2        6.8      899                                      264        10      2       12        682                                      266        10      2        4.3     1186                                      267        10      2        7.5      517                                      268        30      2        7.4      831                                      379        20      2        7        483                                      416        10      2        4.3     1156                                      448        30      2        4.8     1084                                      451        10      2        5.3      989                                      452        10      2        7.8      584                                      453        10      2        9.4      776                                      454        10      2        4       1255                                      455        10      2       13.5      420                                      456        10      2        4.8     1209                                      457        10      2        5.8     1036                                      458        10      2       13.5      537                                      534        10      2       10.6      695                                      ______________________________________                                    

Vasopressin V₁ Antagonist Activity in Conscious Rats

Conscious rats are restrained in a supine position with elastic tape.The area at the base of the tail is locally anesthetized by subcutaneousinfiltration with 2% procaine (0.2 ml). Using aseptic technique theventral caudal tail artery is isolated and a cannula made of PE 10 and20 (heat-fused) tubing is passed into the lower abdominal aorta. Thecannula is secured, heparinized (1000 i.u./cc), sealed and the woundclosed with one or two stitches of Dexon 4-0. The caudal vein is alsocannulated in the same manner for intravenous drug administration. Theduration of the surgery is approximately 5 minutes. Additional localanesthesia (2% procaine or lidocaine) is provided as needed.

The animals are placed in plastic restraining cages in an uprightposition. The cannula is attached to a Statham P23Db pressure transducerand pulsatile blood pressure is recorded. Increase of systolic bloodpressure responses to arginine vasopressin 0.01 and 0.2 internationalunit (I.U.)(350 I.U.=1 mg) injections are recorded prior to any drug(compound) administration, after which each rat is dosed orally withcompounds under study 0.1-100 mg/kg (10 cc/kg) or intravenously 0.1-30mg/kg (1 cc/kg). The vasopressin injections are repeated30,60,90,120,180,240 and 300 min. later. Percentage of antagonism by thecompound is calculated using the pre-drug vasopressin vasopressorresponse as 100%.

The results of this test on representative compounds of this inventionare shown in Table III.

The results of this test on representative compounds of this inventionin which the dose, the maximum % inhibition and the time in minutes, areshown in Table IV.

                                      TABLE III                                   __________________________________________________________________________    VASOPRESSIN (VAS) VASOPRESSOR RESPONSE                                                    VAS Dose                                                                           Min                                                                              Control                                                                           Response                                              Dose        i.u./kg                                                                            Post                                                                             Before                                                                            After    Average                                                                           %                                        (mg/kg)     I.V. Dose                                                                             VAS VAS  Change                                                                            Change                                                                            Inhibition                               __________________________________________________________________________    CONTROL     0.01 0  225 245  20  20                                                               205 225  20                                                           0.02    225 255  30  32.5                                                             205 240  35                                               Vehicle                                                                             10 cc/kg p.o.                                                                       0.01 30 215 240  25  25  -25                                      2% starch           200 225  25                                                           0.02    220 255  35  35  -8                                                           210 245  35                                                           0.01 60 220 240  20  25  -25                                                          200 230  30                                                           0.02    225 260  35  35  -8                                                           215 250  35                                                           0.01 90 210 235  25  22.5                                                                              -13                                                          200 220  20                                                           0.02    235 275  40  37.5                                                                              -15                                                          205 240  35                                                           0.01 120                                                                              225 245  20  22.5                                                                              -13                                                          200 225  25                                                           0.02    225 250  25  35  -8                                                           200 245  45                                                           0.01 180                                                                              210 235  25  20  0                                                            195 210  15                                                           0.02    225 255  30  36  -11                                                          195 237  42                                                           0.01 240                                                                              225 240  15  22.5                                                                              -13                                                          180 210  30                                                           0.02    225 250  25  35  -8                                                           190 235  45                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 420,420 grams           CONTROL     0.05 0  240 270  30  27.5                                                             230 255  25                                                           0.1     230 285  55  45                                                               235 270  35                                               Ex. No. 5                                                                           10 i.v.                                                                             0.05 30 225 260  35  30  -9                                                           235 260  25                                                           0.1     230 2.65 35  35  22                                                           225 260  35                                               Ex. No. 5                                                                           20 i.v.                                                                             0.05 60 245 250  5   10  64                                                           225 240  15                                                           0.1     245 260  15  17.5                                                                              61                                                           235 255  20                                                           0.05 90 225 240  15  10  64                                                           220 225  5                                                            0.1     230 250  20      56                                                           225 245  20                                                           0.05 120                                                                              225 245  20  15  45                                                           225 235  10                                                           0.1     230 245  15  17.5                                                                              61                                                           225 245  20                                                           0.05 180                                                                              225 245  20  12.5                                                                              55                                                           230 235  5                                                            0.1     225 255  30  20  56                                                           240 250  10                                                           0.05 240                                                                              215 235  20  17.5                                                                              36                                                           220 235  15                                                           0.1     215 250  35  25  44                                                           230 245  15                                                           0.05 300                                                                              210 245  35  22.5                                                                              18                                                           245 255  10                                                           0.1     200 235  35  30  33                                                           235 260  25                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 400,400 grams           CONTROL     0.01 0  130 170  40  30                                                               159 179  20                                                           0.02    136 192  56  51                                                               164 210  46                                               Ex. No. 10                                                                          10 i.v.                                                                             0.01 30 136 184  48  37.5                                                                              -25                                                          150 177  27                                                           0.02    136 197  61  64.5                                                                              -26                                                          150 218  68                                               Ex. No. 10                                                                          20 i.v.                                                                             0.01 60 141 156  15  14.5                                                                              52                                                           150 164  14                                                           0.02    138 161  23  22.5                                                                              56                                                           152 174  22                                                           0.01 90 137 154  17  16  47                                                           151 166  15                                                           0.02    135 161  26  23  55                                                           153 173  20                                                           0.01 120                                                                              138 155  17  13.5                                                                              55                                                           150 160  10                                                           0.02    138 161  23  22  57                                                           157 178  21                                                           0.01 180                                                                              132 154  22  25.5                                                                              15                                                           145 174  29                                                           0.02    140 174  34  29.5                                                                              42                                                           157 182  25                                                           0.01 240                                                                              131 156  25  22.5                                                                              25                                                           149 169  20                                                           0.02    140 174  34  34.5                                                                              32                                                           157 192  35                                                           0.01 300                                                                              144 166  22  24.5                                                                              18                                                           151 178  27                                                           0.02    135 170  35  34  33                                                           145 178  33                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 520,470 grams           CONTROL     0.01 0  135 152  17  22.5                                                             132 160  28                                                           0.02    149 216  67  52                                                               137 174  37                                               Ex. No. 14                                                                          10 i.v.                                                                             0.01 30 131 142  11  11  51                                                           143 154  11                                                           0.02    151 173  22  23  56                                                           136 160  24                                                           0.01 60 151 163  12  12  47                                                           139 151  12                                                           0.02    153 171  18  22  58                                                           140 166  26                                                           0.01 90 135 142  7   13.5                                                                              40                                                           140 160  20                                                           0.02    135 173  38  29.5                                                                              43                                                           145 166  21                                                           0.01 120                                                                              137 155  18  16  29                                                           137 151  14                                                           0.02    143 168  25  23.5                                                                              55                                                           139 161  22                                                           0.01 180                                                                              131 153  22  21.5                                                                              4                                                            134 155  21                                                           0.02    140 170  30  30.5                                                                              41                                                           131 162  31                                                           0.01 240                                                                              146 170  24  26.5                                                                              -18                                                          141 166  29                                                           0.02    140 171  30  32  38                                                           141 175  34                                                           0.01 300                                                                              138 160  22  24.5                                                                              -9                                                           142 169  27                                                           0.02    152 186  34  33  37                                                           144 176  32                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weigt(s): 480,420 grams            CONTROL     0.01 0  139 182  43  29.5                                                             128 144  16                                                           0.02    142 182  40  33                                                               162 188  26                                               Ex. No. 16                                                                          30 p.o.                                                                             0.01 30 133 166  33  25  15                                                           148 165  17                                                           0.02    136 163  27  27.5                                                                              17                                                           154 182  28                                                           0.01 60 131 168  37  30.5                                                                              -3                                                           154 178  24                                                           0.02    134 163  29  29  12                                                           162 191  29                                                           0.01 90 137 166  29  28.5                                                                              3                                                            149 177  28                                                           0.02    137 172  35  40.5                                                                              -23                                                          149 195  46                                                           0.01 120                                                                              146 163  17  23.5                                                                              20                                                           148 178  30                                                           0.02    142 166  24  29.5                                                                              11                                                           161 196  35                                                           0.01 180                                                                              142 169  27  30.5                                                                              -3                                                           140 174  34                                                           0.02    138 169  31  26  21                                                           153 174  21                                                           0.01 240                                                                              140 163  23  30  -2                                                           140 177  37                                                           0.02    143 160  17  30  9                                                            157 200  43                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 420,460 grams           CONTROL     0.01 0  147 169  22  21.5                                                             138 159  21                                                           0.02    151 198  47  42                                                               145 182  37                                               Ex. No. 22                                                                          10 i.v.                                                                             0.01 30 152 164  12  8.5 60                                                           146 151  5                                                            0.02    152 177  25  18.5                                                                              56                                                           148 160  12                                                           0.01 60 151 166  15  11  49                                                           144 151  7                                                            0.02    121 144  23  25  40                                                           141 168  27                                                           0.01 90 149 166  17  14  35                                                           140 151  11                                                           0.02    151 166  15  13  69                                                           140 151  11                                                           0.01 120                                                                              138 155  17  17.5                                                                              19                                                           129 147  18                                                           0.02    148 183  35  30  29                                                           141 166  25                                                           0.01 180                                                                              142 168  26  20  7                                                            141 155  14                                                           0.02    150 185  35  36  14                                                           132 169  37                                                           0.01 240                                                                              134 169  35  28  -30                                                          139 169  21                                                           0.02    139 200  61  48  -14                                                          150 185  35                                                           0.01 300                                                                              139 171  32  30  -40                                                          121 149  28                                                           0.02    140 210  70  52.5                                                                              -25                                                          150 185  35                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 450,495 grams           CONTROL     0.01 0  161 191  30  28.5                                                             143 170  27                                                           0.02    157 217  60  51.5                                                             145 188  43                                               Ex. No. 61                                                                          10 i.v.                                                                             0.01 30 158 182  24  21  26                                                           146 164  18                                                           0.02    158 196  38  32.5                                                                              37                                                           146 173  27                                               Ex. No. 61                                                                          20 i.v.                                                                             0.01 60 163 180  17  13  54                                                           147 156  9                                                            0.02    159 179  20  14.5                                                                              72                                                           146 155  9                                                            0.01 90 153 165  12  8   72                                                           150 154  4                                                            0.02    154 173  19  16.5                                                                              68                                                           144 158  14                                                           0.01 120                                                                              151 165  14  12  58                                                           145 155  10                                                           0.02    151 176  25  20  61                                                           143 158  15                                                           0.01 180                                                                              142 165  23  15.5                                                                              46                                                           143 151  8                                                            0.02    148 172  24  17.5                                                                              66                                                           145 156  11                                                           0.01 240                                                                              144 156  12  12  58                                                           144 156  12                                                           0.02    150 179  29  23  55                                                           147 164  17                                                           0.01 300                                                                              142 161  19  15.5                                                                              46                                                           144 156  12                                                           0.02    140 167  27  24  53                                                           153 174  21                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 570,460 grams           CONTROL     0.01 0  139 179  40  39.5                                                             150 189  39                                                           0.02    143 204  61  60.5                                                             156 216  60                                               Ex. No. 62                                                                          10 i.v.                                                                             0.01 30 144 196  52  57  -44                                                          141 203  62                                                           0.02    158 217  59  61.5                                                                              -2                                                           163 227  64                                               Ex. No. 62                                                                          20 i.v.                                                                             0.01 60 131 148  17  13  67                                                           135 144  9                                                            0.02    135 173  38  29.5                                                                              51                                                           134 155  21                                                           0.01 90 132 156  24  23  42                                                           127 149  22                                                           0.02    140 195  55  54  11                                                           136 189  53                                                           0.01 120                                                                              137 160  23  23.5                                                                              41                                                           138 162  24                                                           0.02    143 189  46  50  17                                                           139 193  54                                                           0.01 180                                                                              131 155  24  24.5                                                                              38                                                           133 158  25                                                           0.02    139 155  16  15  75                                                           144 158  14                                                           0.01 240                                                                              126 153  27  30  24                                                           133 166  33                                                           0.02    134 167  33  40.5                                                                              33                                                           142 190  48                                                           0.01 300                                                                              128 152  24  25  37                                                           138 164  26                                                           0.02    140 167  27  38  37                                                           146 195  49                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 500,450 grams           CONTROL     0.01 0  144 177  33  30                                                               128 155  27                                                           0.02    145 1.97 52  46.5                                                             127 168  41                                               Ex. No. 92                                                                          10 i.v.                                                                             0.01 30 155 165  10  10.5                                                                              65                                                           153 164  11                                                           0.02    160 177  17  18.5                                                                              60                                                           155 175  20                                                           0.01 60 143 159  16  18  40                                                           150 170  20                                                           0.02    152 168  16  22  53                                                           149 177  28                                                           0.01 90 145 162  17  17.5                                                                              42                                                           127 145  18                                                           0.02    141 168  27  27  42                                                           144 171  27                                                           0.01 120                                                                              135 156  21  19  37                                                           113 130  17                                                           0.02    134 154  20  20.5                                                                              56                                                           126 147  21                                                           0.01 180                                                                              137 159  22  18  40                                                           144 158  14                                                           0.02    144 180  36  29.5                                                                              37                                                           142 165  23                                                           0.01 240                                                                              149 169  20  19  37                                                           137 155  18                                                           0.02    149 169  20  18  61                                                           146 162  16                                                           0.01 300                                                                              151 171  20  17.5                                                                              42                                                           144 159  15                                                           0.02    158 182  24  24  48                                                           139 163  24                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 440,490 grams           CONTROL     0.01 0  149 177  28  28                                                               149 177  28                                                           0.02    155 196  41  41                                                               155 196  41                                               Ex. No. 121                                                                         10 i.v.                                                                             0.01 30 154 175  21  21  25                                                           154 175  21                                                           0.02    154 190  36  36  12                                                           154 190  36                                               Ex. No. 121                                                                         20 i.v.                                                                             0.01 60 155 168  13  13  54                                                           155 168  13                                                           0.02    156 175  19  19  54                                                           156 175  19                                                           0.01 90 159 172  13  13  54                                                           159 172  13                                                           0.02    157 179  22  22  46                                                           157 179  22                                                           0.01 120                                                                              159 164  5   5   82                                                           159 164  5                                                            0.02    154 173  19  19  54                                                           154 173  19                                                           0.01 180                                                                              151 169  18  18  36                                                           151 169  18                                                           0.02    159 173  14  14  66                                                           159 173  14                                                           0.01 240                                                                              149 169  20  20  29                                                           149 169  20                                                           0.02    151 172  21  21  49                                                           151 172  21                                                           0.01 300                                                                              151 168  17  17  39                                                           151 168  17                                                           0.02    152 177  25  25  39                                                           152 177  25                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 585,410 grams           CONTROL     0.01 0  140 162  22  17.5                                                             147 160  13                                                           0.02    138 169  31  33                                                               141 176  35                                               Ex. No. 123                                                                         10 i.v.                                                                             0.01 30 139 151  12  17.5                                                                              0                                                            154 177  23                                                           0.02    139 177  38  20  39                                                           154 156  2                                                Ex. No. 123                                                                         20 i.v.                                                                             0.01 60 137 140  3   6   66                                                           147 156  9                                                            0.02    132 139  7   6   82                                                           146 151  5                                                            0.01 90 137 141  4   6   66                                                           149 157  8                                                            0.02    135 138  3   7   79                                                           149 160  11                                                           0.01 120                                                                              136 139  3   5   71                                                           147 154  7                                                            0.02    138 141  3   4.5 86                                                           150 156  6                                                            0.01 180                                                                              138 141  3   4   77                                                           150 155  5                                                            0.02    138 142  4   6.5 80                                                           148 157  9                                                            0.01 240                                                                              137 145  8   8   54                                                           146 154  8                                                            0.02    140 146  6   6.5 80                                                           148 155  7                                                            0.01 300                                                                              138 144  6   8   54                                                           144 154  10                                                           0.02    140 148  8   8   76                                                           146 154  8                                                __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 500,480 grams           CONTROL     0.01 0  150 172  22  32.5                                                             140 183  43                                                           0.02    147 187  40  35.5                                                             162 193  31                                               EX. No. 124                                                                         10 i.v.                                                                             0.01 30 150 187  37  38.5                                                                              -18                                                          153 193  40                                                           0.02    148 187  39  43.5                                                                              -23                                                          146 194  48                                               Ex. No. 124                                                                         20 i.v.                                                                             0.01 60 151 155  4   4   88                                                           148 152  4                                                            0.02    150 173  23  17.5                                                                              51                                                           147 159  12                                                           0.01 90 143 159  16  12.5                                                                              62                                                           147 156  9                                                            0.02    148 163  15  18  49                                                           144 165  21                                                           0.01 120                                                                              144 157  13  12.5                                                                              62                                                           147 159  12                                                           0.02    151 167  16  19.5                                                                              45                                                           149 172  23                                                           0.01 180                                                                              131 152  21  21  35                                                           125 146  21                                                           0.02    143 165  22  21.5                                                                              39                                                           143 164  21                                                           0.01 240                                                                              144 163  19  18  45                                                           141 158  17                                                           0.02    147 168  21  24.5                                                                              31                                                           148 176  28                                                           0.01 300                                                                              141 160  19  20  38                                                           138 159  21                                                           0.02    139 176  37  33.5                                                                              6                                                            142 172  30                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 600,550 grams           CONTROL     0.01 0  230 265  35  25                                                               235 250  15                                                           0.02    240 280  40  35                                                               235 265  30                                               Ex. No. 5                                                                           50 p.o.                                                                             0.01 30 250 275  25  22.5                                                                              10                                                           240 260  20                                                           0.02    260 295  35  35  0                                                            235 270  35                                                           0.01 60 240 275  35  30  -20                                                          235 260  25                                                           0.02    260 290  30  35.5                                                                              7                                                            245 280  35                                                           0.01 90 255 270  15  17.5                                                                              30                                                           235 255  20                                                           0.02    260 290  30  32.5                                                                              7                                                            245 280  35                                                           0.01 120                                                                              245 285  40  30  -20                                                          220 240  20                                                           0.02    260 295  35  40  -14                                                          255 270  45                                                           0.01 180                                                                              240 255  15  20  20                                                           220 245  25                                                           0.02    240 270  30  37.5                                                                              -7                                                           250 295  45                                                           0.01 240                                                                              230 255  25  22.5                                                                              10                                                           255 245  20                                                           0.02    260 290  30  38.5                                                                              -10                                                          233 280  47                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 410,430 grams           CONTROL     0.05 0  240 270  30  27.5                                                             230 255  25                                                           0.1     230 285  55  45                                                               235 270  35                                               Ex. No. 5                                                                           10 i.v.                                                                             0.05 30 225 260  35  30  -9                                                           235 260  25                                                           0.01    230 265  35  35  22                                                           225 260  35                                                     20 i.v.                                                                             0.05 60 245 250  5   10  64                                                           225 240  15                                                           0.01    245 260  15  17.5                                                                              61                                                           235 255  20                                                           0.05 90 225 240  15  10  64                                                           220 225  5                                                            0.1     230 250  20  20  56                                                           225 245  20                                                           0.05 120                                                                              225 245  20  15  45                                                           225 235  10                                                           0.1     230 245  15  17.5                                                                              61                                                           225 245  20                                                           0.05 180                                                                              225 245  20  12.5                                                                              55                                                           230 235  5                                                            0.1     225 255  30  20  56                                                           240 250  10                                                           0.05 240                                                                              215 235  20  17.5                                                                              36                                                           220 235  15                                                           0.1     215 250  35  25  44                                                           230 245  15                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 400,400 grams                       0.05 300                                                                              210 245  35  22.5                                                                              18                                                           245 255  10                                                           0.1     200 235  35  30  33                                                           235 260  25                                               CONTROL     0.01 0  130 170  40  30                                                               159 179  20                                                           0.02    136 192  56  51                                                               164 210  46                                               Ex. No. 10                                                                          10 i.v.                                                                             0.01 30 136 184  48  37.5                                                                              -25                                                          150 177  27                                                           0.02    136 197  61  64.5                                                                              -26                                                          150 218  68                                                     20 i.v.                                                                             0.01 60 141 156  15  14.5                                                                              52                                                           150 164  14                                                           0.02    138 161  23  22.5                                                                              56                                                           152 174  22                                                           0.01 90 137 154  17  16  47                                                           151 166  15                                                           0.02    135 161  26  23  55                                                           153 173  20                                                           0.01 120                                                                              138 155  17  13.5                                                                              55                                                           150 160  10                                                           0.02    138 161  23  22  57                                                           157 178  21                                                           0.01 180                                                                              132 154  22  25.5                                                                              15                                                           145 174  29                                                           0.02    140 174  34  29.5                                                                              42                                                           157 182  25                                                           0.01 240                                                                              131 156  25  22.5                                                                              25                                                           149 169  20                                                           0.02    140 174  34  34.5                                                                              32                                                           157 192  35                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 520,470 grams                       0.01 300                                                                              144 166  22  24.5                                                                              18                                                           151 178  27                                                           0.02    135 170  35  34  33                                                           145 178  33                                               CONTROL     0.01 0  135 152  17  22.5                                                             132 160  28                                                           0.02    149 216  67  52                                                               137 174  37                                               Ex. No. 14                                                                          10 i.v.                                                                             0.01 30 131 142  11  11  51                                                           143 154  11                                                           0.02    151 173  22  23  56                                                           136 160  24                                                           0.01 60 151 163  12  12  47                                                           139 151  12                                                           0.02    153 171  18  22  58                                                           140 166  26                                                           0.01 90 135 142  7   13.5                                                                              40                                                           140 160  20                                                           0.02    135 173  38  29.5                                                                              43                                                           145 166  21                                                           0.01 120                                                                              137 155  18  16  29                                                           137 151  14                                                           0.02    143 168  25  23.5                                                                              55                                                           139 161  22                                                           0.01 180                                                                              131 153  22  21.5                                                                              4                                                            134 155  21                                                           0.02    140 170  30  30.5                                                                              41                                                           131 162  31                                                           0.01 240                                                                              146 170  24  26.5                                                                              -18                                                          141 166  29                                                           0.02    140 171  30  32  38                                                           141 175  34                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 480,420 grams                       0.01 300                                                                              138 160  22  24.5                                                                              -9                                                           142 169  27                                                           0.02    152 186  34  33  37                                                           144 176  32                                               CONTROL     0.01 0  139 182  43  29.5                                                             128 144  16                                                           0.02    142 182  40  33                                                               162 188  26                                               Ex. No. 16                                                                          30 p.o.                                                                             0.01 30 133 166  33  25  15                                                           148 165  17                                                           0.02    136 163  27  27.5                                                                              17                                                           154 182  28                                                           0.01 60 131 168  37  30.5                                                                              -3                                                           154 178  24                                                           0.02    134 163  29  29  12                                                           162 191  29                                                           0.01 90 137 166  29  28.5                                                                              3                                                            149 177  28                                                           0.02    137 172  35  40.5                                                                              -23                                                          149 195  46                                                           0.01 120                                                                              146 163  17  23.5                                                                              20                                                           148 178  30                                                           0.02    142 166  24  29.5                                                                              11                                                           161 196  35                                                           0.01 180                                                                              142 169  27  30.5                                                                              -3                                                           140 174  34                                                           0.02    138 169  31  26  21                                                           153 174  21                                                           0.01 240                                                                              140 163  23  30  -2                                                           140 177  37                                                           0.02    143 160  17  30  9                                                            157 200  43                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 420,460 grams           CONTROL     0.01 0  147 169  22  21.5                                                             138 159  21                                                           0.02    151 198  47  42                                                               145 182  37                                               Ex. No. 22                                                                          10 i.v.                                                                             0.01 30 152 164  12  8.5 60                                                           146 151  5                                                            0.02    152 177  25  18.5                                                                              56                                                           148 160  12                                                           0.01 60 151 166  15  11  49                                                           144 151  7                                                            0.02    121 144  23  25  40                                                           141 168  27                                                           0.01 90 149 166  17  14  35                                                           140 151  11                                                           0.02    151 166  15  13  69                                                           140 151  11                                                           0.01 120                                                                              138 155  17  17.5                                                                              19                                                           129 147  18                                                           0.02    148 183  35  30  29                                                           141 166  25                                                           0.01 180                                                                              142 168  26  20  7                                                            141 155  14                                                           0.02    150 185  35  36  14                                                           132 169  37                                                           0.01 240                                                                              134 169  35  28  -30                                                          139 160  21                                                           0.02    139 200  61  48  -14                                                          150 185  35                                                           0.01 300                                                                              139 171  32  30  -40                                                          121 149  28                                                           0.02    140 210  70  52.5                                                                              -25                                                          150 185  35                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 450,495 grams           CONTROL     0.01 0  161 191  30  28.5                                                             143 170  27                                                           0.02    157 217  60  51.5                                                             145 188  43                                               Ex. No. 61                                                                          10 i.v.                                                                             0.01 30 158 182  24  21  26                                                           146 164  18                                                           0.02    158 196  38  32.5                                                                              37                                                           146 173  27                                                     20 i.v.                                                                             0.01 60 163 180  17  13  54                                                           147 156  9                                                            0.02    159 179  20  14.5                                                                              72                                                           146 155  9                                                            0.01 90 153 165  12  8   72                                                           150 154  4                                                            0.02    154 173  19  16.5                                                                              68                                                           144 158  14                                                           0.01 120                                                                              151 165  14  12  58                                                           145 155  10                                                           0.02 151                                                                              176 25   20  61                                                               143 158  15                                                           0.01 180                                                                              142 165  23  15.5                                                                              46                                                           143 151  8                                                            0.02    148 172  24  17.5                                                                              66                                                           145 156  11                                                           0.01 240                                                                              144 156  12  12  58                                                           144 156  12                                                           0.02    150 179  29  23  55                                                           147 164  17                                                           0.01 300                                                                              142 161  19  15.5                                                                              46                                                           144 156  12                                                           0.02    140 167  27  24  53                                                           153 174  21                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 570,460 grams           CONTROL     0.01 0  139 179  40  39.5                                                             150 189  39                                                           0.02    143 204  61  60.5                                                             156 216  60                                               Ex. No. 62                                                                          10 i.v.                                                                             0.01 30 144 196  52  57  -44                                                          141 203  62                                                           0.02    158 217  59  61.5                                                                              -2                                                           163 227  64                                                     20 i.v.                                                                             0.01 60 131 148  17  13  67                                                           135 144  9                                                            0.02    135 173  38  29.5                                                                              51                                                           134 155  21                                                           0.01 90 132 156  24  23  42                                                           127 149  22                                                           0.02    140 195  55  54  11                                                           136 189  53                                                           0.01 120                                                                              137 160  23  23.5                                                                              41                                                           138 162  24                                                           0.02    143 189  46  50  17                                                           139 193  54                                                           0.01 180                                                                              131 155  24  24.5                                                                              38                                                           133 158  25                                                           0.02    139 155  16  15  75                                                           144 158  14                                                           0.01 240                                                                              126 153  27  30  24                                                           133 166  33                                                           0.02    134 167  33  40.5                                                                              33                                                           142 190  48                                                           0.01 300                                                                              128 152  24  25  37                                                           138 164  26                                                           0.02    140 167  27  38  37                                                           146 195  49                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 500,450 grams           CONTROL     0.01 0  144 177  33  30                                                               128 155  27                                                           0.02    145 197  52  46.5                                                             127 168  41                                               Ex. No. 92                                                                          10 i.v.                                                                             0.01 30 155 165  10  10.5                                                                              65                                                           153 164  11                                                           0.02    160 177  17  18.5                                                                              60                                                           155 175  20                                                           0.01 60 143 159  16  18  40                                                           150 170  20                                                           0.02    152 168  16  22  53                                                           149 177  28                                                           0.01 90 145 162  17  17.5                                                                              42                                                           127 145  18                                                           0.02    141 168  27  27  42                                                           144 171  27                                                           0.01 120                                                                              135 156  21  19  37                                                           113 130  17                                                           0.02    134 154  20  20.5                                                                              56                                                           126 147  21                                                           0.01 180                                                                              137 159  22  18  40                                                           144 158  14                                                           0.02    144 180  36  29.5                                                                              37                                                           142 165  23                                                           0.01 240                                                                              149 169  20  19  37                                                           137 155  18                                                           0.02    149 169  20  18  61                                                           146 162  16                                                           0.01 300                                                                              151 171  20  17.5                                                                              42                                                           144 159  15                                                           0.02    158 182  24  24  48                                                           139 163  24                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 440,490 grams           CONTROL     0.01 0  149 177  28  28                                                               149 177  28                                                           0.02    155 196  41  41                                                               155 196  41                                               Ex. No. 121                                                                         10 i.v.                                                                             0.01 30 154 175  21  21  25                                                           154 175  21                                                           0.02    154 190  36  36  12                                                           154 190  36                                                     20 i.v.                                                                             0.01 60 155 168  13  13  54                                                           155 168  13                                                           0.02    156 175  19  19  54                                                           156 175  19                                                           0.01 90 159 172  13  13  54                                                           159 172  13                                                           0.02    157 179  22  22  46                                                           157 179  22                                                           0.01 120                                                                              159 164  5   5   82                                                           159 164  5                                                            0.02    154 173  19  19  54                                                           154 173  19                                                           0.01 180                                                                              151 169  18  18  36                                                           151 169  18                                                           0.02    159 173  14  14  66                                                           159 173  14                                                           0.01 240                                                                              149 169  20  20  29                                                           149 169  20                                                           0.02    151 172  21  21  49                                                           151 172  21                                                           0.01 300                                                                              151 168  17  17  39                                                           151 168  17                                                           0.02    152 177  25  25  39                                                           152 177  25                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 585,410 grams           CONTROL     0.01 140                                                                              162 22   17.5                                                                 147 160  13                                                           0.02    138 169  31  33                                                               141 176  35                                               Ex. No. 123                                                                         10 i.v.                                                                             0.01 30 139 151  12  17.5                                                                              0                                                            154 177  23                                                           0.02    139 177  38  20  39                                                           154 156  2                                                      20 i.v.                                                                             0.01 60 137 140  3   6   66                                                           147 156  9                                                            0.02    132 139  7   6   82                                                           146 151  5                                                            0.01 90 137 141  4   6   66                                                           149 157  8                                                            0.02    135 138  3   7   79                                                           149 160  11                                                           0.01 120                                                                              136 139  3   5   71                                                           147 154  7                                                            0.02    138 141  3   4.5 86                                                           150 156  6                                                            0.01 180                                                                              138 141  3   4   77                                                           150 155  5                                                            0.02    138 142  4   6.5 80                                                           148 157  9                                                            0.01 240                                                                              137 145  8   8   54                                                           146 154  8                                                            0.02    140 146  6   6.5 80                                                           148 155  7                                                            0.01 300                                                                              138 144  6   8   54                                                           144 154  10                                                           0.02    140 148  8   8   76                                                           146 154  8                                                __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight,(s): 500,480 grams          CONTROL     0.01 0  150 172  22  32.5                                                             140 183  43                                                           0.02    147 187  40  35.5                                                             162 193  31                                               Ex. No. 124                                                                         10 i.v.                                                                             0.01 30 150 187  37  38.5                                                                              -18                                                          153 193  40                                                           0.02    148 187  39  43.5                                                                              -23                                                          146 194  48                                                     20 i.v.                                                                             0.01 60 151 155  4   4   88                                                           148 152  4                                                            0.02    150 173  23  17.5                                                                              51                                                           147 159  12                                                           0.01 90 143 159  16  12.5                                                                              62                                                           147 156  9                                                            0.02    148 163  15  18  49                                                           144 165  21                                                           0.01 120                                                                              144 157  13  12.5                                                                              62                                                           147 159  12                                                           0.02    151 167  16  19.5                                                                              45                                                           149 172  23                                                           0.01 180                                                                              131 152  21  21  35                                                           125 146  21                                                           0.02    143 165  22  21.5                                                                              39                                                           143 164  21                                                           0.01 240                                                                              144 163  19  18  45                                                           141 158  17                                                           0.02    147 168  21  24.5                                                                              31                                                           148 176  28                                                           0.01 300                                                                              141 160  19  20  38                                                           138 159  21                                                           0.02    139 176  37  33.5                                                                              6                                                            142 172  30                                               __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 600,550                 __________________________________________________________________________    grams                                                                     

                  TABLE IV                                                        ______________________________________                                        VASOPRESSIN (VAS) VASOPRESSOR RESPONSE                                        Ex. No.  Dose mg/kg MAX % Inhibition                                                                           Time (Min)                                   ______________________________________                                         2       10 p.o.    65           180                                          136      10 i.v.    81            30                                          137      10 i.v.    52            30                                          138      10 i.v.    88            60                                          167      10 i.v.    70           180                                          251      30 i.v.    41            60                                          252      30 i.v.    75           120                                          253      30 i.v.    57           180                                          254      30 i.v.    74            60                                          255      10 i.v.    65            60                                          257      10 i.v.    71            60                                          258      30 i.v.    61            60                                          259      30 i.v.    29            90                                          260      30 i.v.    79           120                                          261      10 i.v.    74            60                                          263      10 i.v.    55            90                                          266      30 i.v.    21           120                                          267      10 i.v.    74           120                                          268      10 i.v.    85            90                                          379      10 i.v.    75           300                                          416      30 i.v.    44            90                                          448      30 i.v.    60            90                                          449      10 i.v.    45            90                                          455      30 i.v.    46           120                                          457      10 i.v.    61           300                                          458      10 i.v.    77           180                                          ______________________________________                                    

Oxytocin Receptor Binding

(a) Membrane Preparation

Female Sprague-Dawley rats weighing approximately 200-250 g are injectedintramuscularly (i.m.) with 0.3 mg/kg of body weight ofdiethylstilbestrol (DES). The rats are sacrificed 18 hours later underpentobarbital anesthesia. The uteri are dissected out, cleaned of fatand connective tissues and rinsed in 50 ml of normal saline. The tissuepooled from six rats is homogenized in 50 ml of 0.01 mM Tris.HCl,containing 0.5 mM dithiothreitol and 1.0 mM EDTA, adjusted to pH 7.4,using a polytron at setting 6 with three passes of 10 sec each. Thehomogenate is passed through two (2) layers of cheesecloth and thefiltrate centrifuged at 1000×g for 10 min. The clear supernatant isremoved and recentrifuged at 165,000×g for 30 min. The resulting pelletcontaining the oxytocin receptors is resuspended in 50.0 mM Tris. HClcontaining 5.0 mM MgCl₂ at pH 7.4, to give a protein concentration of2.5 mg/ml of tissue suspension. This preparation is used in subsequentbinding assays with ³ H!Oxytocin.

(b) Radioligand Binding

Binding of 3,5- ³ H!Oxytocin ( ³ H!OT) to its receptors is done inmicrotiter plates using ³ H!OT, at various concentrations, in an assaybuffer of 50.0 mM Tris.HCl, pH 7.4 and containing 5.0 mM MgCl₂, and amixture of protease inhibitors: BSA, 0.1 mg; aprotinin, 1.0 mg;1,10-phenanthroline, 2.0 mg; trypsin, 10.0 mg; and PMSF, 0.3 mg per 100ml of buffer solution. Non-specific binding is determined in thepresence of 1.0 uM unlabeled OT. The binding reaction is terminatedafter 60 min., at 22° C., by rapid filtration through glass fiberfilters using a Brandel® cell harvester (Biomedical Research andDevelopment Laboratories, Inc., Gaithersburg, Md.). Competitionexperiments are conducted at equilibrium using 1.0 nM ³ H!OT and varyingthe concentration of the displacing agents. The concentrations of agentdisplacing 50% of ³ H!OT at its sites (IC₅₀) are calculated by acomputer assisted LUNDON-2 program (LUNDON SOFTWARE INC., Ohio, USA).

The results of this assay on representative examples are shown in TableV.

                  TABLE V                                                         ______________________________________                                        Oxytocin                                                                               Dose         % Inhibition                                            Ex. No.  (μM)      at 10 μM                                                                             IC.sub.50                                     ______________________________________                                         2       10           73        2.9                                            5       10           90        2                                              11      10           71        4.4                                           249      10           38                                                      250      10           15                                                      251      10           77                                                      253      10           77        3.1                                           254      10           95        1.9                                           255      10           99        0.46                                          256      10           47        6.5                                           257      10           97        0.189                                         258      10           18                                                      259      10            7                                                      260      10           44                                                      261      10           97        0.21                                          262      10           55        6.2                                           263      10           94        0.26                                          264       1           34                                                      266      10           15                                                      267      10           89        1.1                                           268      10           89        2.4                                           345      10            2                                                      379      10           96        0.81                                          416      10           19                                                      448      10           39                                                      450      10           33                                                      451       1            0                                                      452       1           22                                                      453       5           53        3.3                                           454      10           78        2.5                                           455      10           88        1.1                                           534      10           86        0.94                                          582                             2.8                                           583      10           58                                                      585                             0.32                                          ______________________________________                                    

The compounds of the present invention can be used in the form of saltsderived from pharmaceutically or physiologically acceptable acids orbases. These salts include, but are not limited to, the following: saltswith inorganic acids such as hydrochloric acid, sulfuric acid, nitricacid, phosphoric acid and, as the case may be, such organic acids asacetic acid, oxalic acid, succinic acid, and maleic acid. Other saltsinclude salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium or with organic bases. Thecompounds can also be used in the form of esters, carbamates and otherconventional "pro-drug" forms, which, when administered in such form,convert to the active moiety in vivo. When the compounds are employedfor the above utility, they may be combined with one or morepharmaceutically acceptable carriers, for example, solvents, diluentsand the like, and may be administered orally in such forms as tablets,capsules, dispersible powders, granules, or suspensions containing, forexample, from about 0.05 to 5% of suspending agent, syrups containing,for example, from about 10 to 50% of sugar, and elixirs containing, forexample, from about 20 to 50% ethanol, and the like, or parenterally inthe form of sterile injectable solution or suspension containing fromabout 0.05 to 5% suspending agent in an isotonic medium. Suchpharmaceutical preparations may contain, for example, from about 0.05 upto about 90% of the active ingredient in combination with the carrier,more usually between about 5% and 60% by weight.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.5 to about 500 mg/kgof animal body weight, preferably given in divided doses two to fourtimes a day, or in a sustained release form. For most large mammals thetotal daily dosage is from about 1 to 100 mg, preferably from about 2 to80 mg. Dosage forms suitable for internal use comprise from about 0.5 to500 mg of the active compound in intimate admixture with a solid orliquid pharmaceutically acceptable carrier. This dosage regimen may beadjusted to provide the optimal therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oi8ls suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparation contain a preservative to prevent thegrowth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol(e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Reference Example 1 6,11-Dihydro-5H-dibenz b,e!azepine

A mixture of 48.52 g (0.20 mol) of 2-aminobenzophenone-2'-carboxylicacid and 500 ml of xylene is refluxed for 67 hours, cooled to roomtemperature and filtered. The solid is washed with xylene to give 43.3 g(97.8%) of 5H-dibenz b,e!azepine-6,11-dione as light tan crystals, m.p.245°-248° C. To 4.46 g (0.020 mol) of the preceding compound in 25 ml oftetrahydrofuran is added 12 ml (0.12 mol) of a 10 molar solution ofboron-dimethylsulfide in tetrahydrofuran. An additional 10 ml oftetrahydrofuran is added and the mixture is stirred overnight and thenis refluxed (solids dissolve) for 4 hours. The solution is cooled and 15ml of methanol added dropwise. The mixture is concentrated under vacuum,50 ml of 2N sodium hydroxide is added and the mixture refluxed for 2hours. The solid is filtered, washed with water, air dried and extractedwith dichloromethane. The extract is dried (Na₂ SO₄) and the solventremoved to give 3.25 g (83%) of crystals, m.p. 117°-122° C.

Reference Example 2 4- (2-Methylbenzoyl)amino!benzoic acid

A mixture of 43.42 g (0.26 mol) of ethyl 4-aminobenzoate and 40.8 g(0.26 mol) of 2-methylbenzoyl chloride in 150 ml of dichloromethane iscooled in an ice bath and 26.56 g (0.26 mol) of triethylamine is addeddropwise. After the addition, the solution is stirred at roomtemperature overnight. The mixture is poured into water and the organiclayer separated. The organic layer is washed with water, 1N HCl, 1MNaHCO₃ and dried (Na₂ SO₄). The solvent is removed and the solidslurried with ethyl acetate and filtered to give 57 g of ethyl 4-(2-methylbenzoyl)amino!benzoate as crystals, m.p. 110°-115° C.

A mixture of 50.7 g (0.20 mol) of the preceding compound, 280 ml ofethanol and 55 ml of 10N NaOH is refluxed for 5 minutes. The mixture iscooled to room temperature, diluted with 200 ml of water and acidifiedwith concentrated hydrochloric acid (pH 1-2). The mixture is filteredand the solid washed with water and dried to give 51 g of product aswhite crystals, m.p. 270°-275° C.

Reference Example 3 4- (2-Methylbenzoyl)amino!benzoyl chloride

A mixture of 10.3 g of 4- (2-methylbenzoyl)amino!benzoic acid and 32 mlof thionyl chloride is refluxed for 1.5 hours. The solution isconcentrated under vacuum. Toluene is added and the solvent removedunder vacuum. Toluene is added and the mixture chilled and filtered togive a yellow solid, m.p. 135°-141° C.

Reference Example 4 4- (2,6-Dimethoxybenzoyl)amino!benzoic acid

A mixture of 2 g (10 mmol) of 2,6-dimethoxybenzoyl chloride, 1.65 g (10mmol) of ethyl 4-aminobenzoate, 1.11 g of triethylamine and 61 mg of4-dimethylaminopyridine in 10 ml of dichloromethane is refluxed for 20hours. The mixture is diluted with water and the organic layer separate.The organic layer is washed with water, 1N HCl, 1N Na₂ CO₃, brine anddried (Na₂ SO₄). The solvent is removed to give a solid which iscrystallized from ethyl acetate to give 1.22 g of ethyl 4-(2,6-dimethoxybenzoyl)amino!benzoate as crystals, m.p. 183°-185° C.

A mixture of 3.88 g (11.79 mmol) of the preceding compound, 17.3 ml of2N NaOH and 20 ml of methanol is stirred at room temperature overnight.Methanol (30 ml) and water (10 ml) are added and the solution refluxedfor 1/2 hour. The solvents are removed under vacuum and the residualsolid triturated with ether and the ether decanted. The solid isdissolved in 30 ml of water and acidified with 2N HCl (pH 3). Themixture is filtered, the solid washed with water and dried at 60° C.under vacuum to give 3.0 g of solid, m.p. 236°-240° C.

Reference Example 5 4- (4-Pyridinylcarbonyl)amino!benzoic acid

To a cooled mixture of 1.78 g (0.01 mol) of isoniconinoyl chloridehydrochloride in 5 ml of dichloromethane is added 2.52 g (0.025 mol) oftriethylamine. To the solution is added a solution of 1.65 g of ethyl4-aminobenzoate in 5 ml of dichloromethane. After stirring at roomtemperature overnight, 50 mg of 4-dimethylaminopyridine is added and themixture is refluxed for 24 hours. The mixture is poured into water andfiltered to give 3.4 g of brown solid. A 0.50 g sample is trituratedwith ethyl acetate to give 0.37 g of ethyl 4-(4-pyridinylcarbonyl)amino!benzoate as yellow crystals, m.p. 143°-145°C. Anal. Calc'd for C₁₅ H₁₄ N₂ O₃ : C,66.7; H,5.2; N,10.4 Found: C,66.4;H,5.1; N,10.3.

A solution of 8.15 g (30 mmol) of the preceding compound and 22 ml of 2NNaOH in 60 ml of methanol is heated on a steam bath for 1 hour. Themixture is cooled and filtered to the solid in water is added 2N citricacid. Stirring and filtering gives 4.24 g of crystals, m.p. 362°-365° C.Anal. Calc'd for C₁₃ H₁₀ N₂ O₃ 1/2 H₂ O C,62.1; H,4.4; N,11.1 Found:62.6; H,4.3; N,11.0.

Reference Example 6 4- (3-Pyridinylcarbonyl)amino!benzoic acid

A mixture of 1.83 g (0.01 mol) of nicotinoyl chloride hydrochloride(97%), 1.65 g of (0.01 mol) of ethyl 4-aminobenzoate, 2.22 g (0.022 mol)of triethylamine and 61 mg of 4-dimethylaminopyridine in 33 ml ofdichloromethane is refluxed 24 hours. The solution is washed with water,2N citric acid and NaHCO₃ solution. The solvent is removed and theresidue triturated with methanol to give 2.3 g of ethyl 4-(3-pyridinylcarbonyl)amino!benzoate as yellow crystals, m.p. 125°-127°C.

A mixture of 12.0 g (0.044 mol) of ethyl 4-(3-pyridinylcarbonyl)amino!benzoic acid, 65 ml of 2N sodium hydroxideand 120 ml of methanol is refluxed for 0.75 hour. The solvent is removedand the residue extracted with diethyl ether. The residue is dilutedwith water and solid citric acid is added until the pH is 4-5. Themixture is filtered and the solid washed with water and air dried togive crystals, m.p. 307°-310° C.

Reference Example 7 5,6-Dihydro-5-(4-nitrobenzoyl)phenanthridine

To a suspension of 7.5 g of 5,6-dihydrophenanthridine in 40 ml of warmpyridine under nitrogen is added 3.6 g of 4-nitrobenzoyl chloride. Themixture is stirred overnight, filtered and the solid washed twice with 5ml of pyridine. To the filtrate is added 250 ml of 2N HCl and themixture stirred and then filtered to give 6.6 g of solid. This solid isheated with 25 ml of ethyl acetate and filtered. The filtrate is dilutedwith 25 ml of hexane and filtered. The filtrate is chromatographed HPLCon a Waters-Prep 500 instrument with two silica gel columns andhexane-ethyl acetate (4:1) as solvent. Cuts containing product arecombined to give 2.3 g of yellow crystals, m.p. 153° to 154° C. Anal.Calc'd for C₂₀ H₁₄ N₂ O₃ : C,72.7; H,4.3; N,8.5 Found: 72.0; H,4.3;N,8.3.

Reference Example 8 5-(4-Aminobenzoyl)-5,6-dihydrophenanthridine

A solution of 2.15 g of 5,6-dihydro-5-(4-nitrobenzoyl)phenanthridine in50 ml of ethyl acetate and 0.5 g of 10% palladium-on-carbon ishydrogenated in a Parr apparatus under an atmosphere of hydrogen forthree hours. The mixture is filtered through diatomaceous earth and thesolvent removed to give 1.7 g of the product as a yellow foam.

Reference Example 9 6,11-Dihydro-5-(4-nitrobenzoyl)-5H-dibenzb,e!-azepine

A mixture of 2.34 g (12 mmol) of 6,11-dihydro-5H-dibenz b,e!azepine,2.23 g (12 mmol) of 4-nitrobenzoyl chloride, 1.94 g (15 mmol) ofdiisopropylethylamine and 70.5 mg of 4-(dimethylamino)pyridine in 25 mlof dichloromethane is stirred at room temperature for 2 hours, refluxedfor 3 hours and allowed to stand at room temperature for 2 days. Themixture is washed with water, 1N sodium bicarbonate, water, 1N HCl,brine and dried (Na₂ SO₄). The solvent is removed to give 4.0 g ofsolid. Trituration with ethyl acetate and filtering gives 2.85 g ofoff-white crystals, m.p. 185°-188° C. Anal. Calc'd for C₂₁ H₁₆ N₂ O₃ 0.5H₂ O: C,71.4; H,4.7; N,7.9. Found: C,71.5; H,4.5; N,7.9.

Reference Example 10 5-(4-Aminobenzoyl)-6,11-dihydro-5H-dibenzb,e!azepine

To a solution of 4.5 g of 6,11-dihydro-5-(4-nitrobenzoyl)-5H-dibenzb,e!azepine in 230 ml of glacial acetic acid is added 0.58 g of 10%palladium-on-carbon and the mixture under hydrogen (38 psi) shaken in aParr hydrogenator for 6.5 hours. The mixture is filtered throughdiatomaceous earth and the filtrate concentrated to give 4.0 g of solid.The solid is extracted with 100 ml of dichloromethane and the extractwashed with water, dried (Na₂ SO₄). The solvent is removed to give 4.0 gof yellow crystals, m.p. 168°-175° C. A sample chromatographed on athick layer silica gel plate with hexane-ethyl acetate (8:7) as solventgives yellow crystals, m.p. 173°-175° C. Anal. Calc'd for C₂₁ H₁₈ N₂ O:C,80.2; H,5.8; N,8.9. Found: C,79.2; H,6.0; N,8.8.

Reference Example 11 2-Chloro-5H-dibenz b,e!azepine-6,11-dione

Chlorine gas is bubbled into a mixture (partial suspension) of 1.0 g(450 mmol) of 5H-dibenz b,e!-azepine-6,11-dione in 50 ml of glacialacetic acid. The temperature of the mixture rises to 38° C. On standing,as the temperature of the solutions decreases, a white solidprecipitates. The mixture is filtered to give 0.40 g of solid (mixtureof starting material and product in ratio of 1:8). The filtrate onstanding gives 0.10 g of product as crystals, m.p. 289°-293° C.

Reference Example 12 10,11-Dihydro-N,N-dimethyldibenz b,f!1,4!oxazepine-2-sulfonamide

To 5.88 g of 10,11-dihydro-N,N-dimethyl-11-oxodibenz b,f!1,4!oxazepine-2-sulfonamide in 5 ml of tetrahydrofuran is added 20 ml ofa molar solution of borane-dimethylsulfide in tetrahydrofuran. Themixture is stirred overnight and then refluxed for 2 hours. The mixtureis chilled, diluted with 10 ml of methanol and then concentrated,methanol added again and the mixture concentrated. To the mixture isadded 20 ml of 2N NaOH and the mixture refluxed for 2 hours. The mixtureis extracted with dichloromethane, the extract dried (MgSO₄) andfiltered. The filtrate is passed through a thin pad of hydrous magnesiumsilicate and the pad washed with dichloromethane. The filtrate isconcentrated to give 4.8 g of crystals, m.p. 99°-102° C.Recrystallization from diisopropylether-dichloromethane gives 3.96 g ofcrystals, m.p. 109°-110° C. Mass Spectrum (FAB) 305(M+H). Anal. Calc'dfor C₁₅ H₁₆ N₂ O₃ S: C,59.2; H,5.3; N,9.2; S,10.6. Found: C,57.6; H,5.2;N,8.9; S,10.1.

Reference Example 1310,11-Dihydro-N,N-dimethyl-10-(4-nitrobenzoyl)-dibenz b,f!1,4!oxazepine-2-sulfonamide

A mixture of 0.9 g of 10,11-dihydro-N,N-dimethyldibenz b,f!1,4!oxazepine-2-sulfonamide and 0.55 g of 4-nitrobenzoyl chloride in 3ml of pyridine is stirred for 7 hours. To the mixture is added 20 ml of2N hydrochloric acid and the mixture is extracted with ethyl acetate.The extract is washed with 5 ml of 2N HCl and three times with 5 ml of2N Na₂ CO₃. The extract is dried (MgSO₄) and filtered through a thin padof hydrous magnesium silicate. The pad is washed with ethyl acetate andthe filtrate concentrated to give 1.1 g of a yellow solid.Crystallization from dichloromethane-diisopropylether gives 0.62 g ofcrystals, m.p. 177°-178° C.

Reference Example 14 2-Chloro-5,6-dihydrophenanthridine

To a hot (70° C.) solution of 2.62 g (17 mmol) of 6(5H)-phenanthridinonein 120 ml of acetic acid is added chlorine gas for 10 minutes. Thesolution is allowed to cool to room temperature and the mixturefiltered. The crystals are filtered to give 1.35 g of crystals, m.p.310°-318° C.

To the preceding compound (1.57 g) in 25 ml of tetrahydrofuran is added12 ml of a 10 molar solution of boron-dimethylsulfide intetrahydrofuran. The mixture is refluxed for 18 hours, cooled and 15 mlof methanol is added. The mixture is concentrated under vacuum and 50 mlof 2 N sodium hydroxide added. The mixture is refluxed for 2 hours andthe solid filtered off and washed with water and air dried to give theproduct as a solid.

Reference Example 15 9-Chloro-5H-dibenz b,e!azepin-6,11-dione

A mixture of 11.15 g of 5H-dibenz b,e!azepin-6,11-dione and 600 ml ofglacial acetic acid is heated on a steam bath until the solid dissolves.To the solution (70° C.) is added chlorine gas. chlorine is bubbledthrough the solution until a precipitate begins to form. The mixture isallowed to cool to room temperature and is filtered to give 7.3 g ofproduct, m.p. 290° C. to 295° C.

Reference Example 16 9-Chloro-6,11-dihydro-5H-dibenz b,e!azepine

To a mixture of 7.28 g of 9-chloro-5H-dibenz b,e!azepin-6,11-dione in 25ml of tetrahydrofuran under argon is added 8.5 ml of 10 molarboron-dimethylsulfide in tetrahydrofuran. The mixture is stirred 18hours at room temperature, 30 ml of tetrahydrofuran added and themixture refluxed for 3 hours (solids dissolved). The solution is cooledto room temperature and 25 ml of methanol added dropwise. The volatilesare removed under vacuum. To the residue is added 100 ml of 2N NaOH. Themixture is refluxed overnight and filtered. The solid is extracted withdichloromethane and the extract is washed with 2N citric acid, water anddried (Na₂ SO₄). The solvent is removed to give 4.2 g of solid which istriturated with ethyl acetate-hexane (1:2) to give crystals, m.p. 137°C. to 141° C.

Reference Example 17 10.11-Dihydrodibenz b,f! 1,4!thiazepine

To a mixture of 3.3 g of 10,11-dihydro-11-oxodibenz b,f! 1,4!thiazepinein 25 ml of tetrahydrofuran is added 4.0 ml of 10 molarborane-dimethylsulfide in tetrahydrofuran. The mixture is stirred atroom temperature for 18 hours, 50 ml of anhydrous methanol added and thesolvent removed. An additional 30 ml of methanol is added and thesolvent removed to give white crystals. A sample is purified bychromatography on silica gel with hexane-chloroform-ethyl acetate(2:1:1) as solvent to give white crystals, m.p. 145°-148° C.

The following compounds are prepared as described in Reference Example17.

Reference Example 28 4-Methyl-10,11-dihydrodibenz b,f! 1,4!thiazepineReference Example 19 4-Chloro-10,11-dihydrodibenz b,f! 1,4!thiazepineReference Example 20 2-Methyl-10,11-dihydrodibenz b,f! 1,4!thiazepineReference Example 21 2-Chloro-10,11-dihydrodibenz b,f! 1,4!thiazepineReference Example 22 2-Methoxy-10,11-dihydrodibenz b,f! 1,4!thiazepineReference Example 23 8-Chloro-10,11-dihydrodibenz b,f! 1,4!thiazepineReference Example 24 4,8-Dichloro-10,11-dihydrodibenz b,f!1,4!thiazepine Reference Example 258-Chloro-4-methyl-10,11-dihydrodibenz b,f! 1,4!thiazepine ReferenceExample 26 8-Methoxy-10,11-dihydrodibenz b,f! 1,4!thiazepine ReferenceExample 27 7-Chloro-4-methyl-10,11-dihydrodibenz b,f! 1,4!thiazepine

The following compounds are prepared as described in Reference Example12.

Reference Example 28 2-Chloro-10,11-dihydrodibenz b,f! 1,4!-oxazepineReference Example 29 2-Methyl-10,11-dihydrodibenz b,f! 1,4!-oxazepineReference Example 30 4-Chloro-10,11-dihydrodibenz b,f! 1,4!-oxazepineReference Example 31 3-Methyl-10,11-dihydrodibenz b,f! 1,4!-oxazepineReference Example 32 7-Chloro-10,11-dihydrodibenz b,f! 1,4!-oxazepineReference Example 33 8-Chloro-10,11-dihydrodibenz b,f! 1,4!-oxazepineReference Example 34 2,4-Dichloro-10,11-dihydrodibenz b,f!1,4!-oxazepine Reference Example 35 4,8-Dichloro-10,11-dihydrodibenzb,f! 1,4!-oxazepine Reference Example 364-Chloro-8-methyl-10,11-dihydrodibenz b,f! 1,4!-oxazepine ReferenceExample 37 4-Methyl-7-chloro-10,11-dihydrodibenz b,f! 1,4!-oxazepineReference Example 38 1-Chloro-4-methyl-10,11-dihydrodibenz b,f!1,4!-oxazepine Reference Example 39 2-Fluoro-10,11-dihydrodibenz b,f!1,4!-oxazepine Reference Example 40N-(2-Iodophenyl)-2-iodophenylacetamide

A solution of 13.32 g (0.05 mol) of 2-iodophenylacetic acid in 75 mlthionyl chloride is refluxed for 2 hours, and the volatiles removedunder vacuum. Toluene is added (3 times) and the solvent removed undervacuum after each addition to give 2-iodophenylacetyl chloride as a gum.To the preceding compound (0.05 mol) in a mixture of 100 ml oftoluene-dichloromethane (1:1) is added 11 g (0.05 mol) of 2-iodoanilineand (0.10 mol) of diisopropylethylamine. The mixture is stirred at roomtemperature overnight and the solvent removed. The residue is dissolvedin dichloromethane and the solution washed with 1N HCl, saturated sodiumbicarbonate, brine and dried (Na₂ SO₄). The solvent is removed and theresidue recrystallized from methanol-ether to give 16.0 g of light browncrystals, m.p. 160°-163° C.

Reference Example 41 2-Iodo-N-(2-iodophenyl)benzeneethanamine

To a suspension of 1.39 g (3 mmol) of2-iodo-N-(2-iodophenyl)benzeneacetamide in 30 ml oftetrahydrofuran-dichloromethane (1:1) is added 3.75 ml of 2.0 molarborane-dimethylsulfide in tetrahydrofuran. The solution is stirred 1 hrat room temperature and then refluxed for 16 hours. The mixture iscooled and water slowly added dropwise until gas evolution ceases. Thevolatiles are removed under vacuum and the aqueous residue made alkalinewith 2N sodium hydroxide. The mixture is extracted with ether (50 ml)and the extract is washed with brine and dried (Na₂ SO₄). The solutionis filtered through a thin pad hydrous magnesium silicate and the filterpad is washed with ether and the filtrate evaporated. The residual solidis washed with isooctane to give 1.20 g of white solid.Recrystallization from diethylether/hexane gives white crystals.

Reference Example 42N-(4-Nitrobenzoyl-N-(2-iodophenyl)-2-iodobenzeneethylamine

To a solution of 0.90 g of 2-iodo-N-(2-iodophenyl)benzeneethanamine in 4ml of tetrahydrofuran is added 0.41 g of triethylamine, and 0.57 g of4-nitrobenzoyl chloride. The mixture is stirred at room temperature for2 hours and the solvent removed under vacuum. The residue is dissolvedin ethyl acetate-dichloromethane (5:1) and the solution washed with 1NHCl, saturated NaHCO₃, brine and dried (Na₂ SO₄). The solution isfiltered through a thin pad of hydrous magnesium silicate. The filtrateis evaporated and the residual solid triturated with diethyl ether andhexane to give 1.10 g of product as a white solid.

Reference Example 43 5-(4-Nitrobenzoyl)-6,7-dihydro-5H-dibenzb,d!azepine

To a solution of 0.90 g ofN-(4-nitrobenzoyl)-N-(2-iodophenyl)-2-iodobenzeneethylamine in 10 ml ofN,N-dimethylpropyleneurea (DMPU) is added 1.91 g of "activated" copperbronze. The mixture is stirred and heated at 195° for 2 days, cooled andslowly dropped into 100 ml of 0.5N HCl with stirring. The precipitate isfiltered, washed with H₂ O and air dried (1.0 g of solid). The solid isextracted with ethyl acetate to give 0.50 g of solid. Chromatography onthick layer silica gel plates with ethyl acetate-hexane (1:2) as solventgives 0.15 g of yellow solid.

Reference Example 44 5-(4-Aminobenzoyl)-6,7-dihydro-5H-dibenzb,d!azepine

A solution of 0.15 g of 5-(4-nitrobenzoyl)-6,7-dihydro-5H-dibenzb,d!azepine in 20 μl of ethanolethyl acetate and 10 mg of 10%palladium-on-carbon is hydrogenated under 35 pounds per square inch ofhydrogen for 8 hr. The mixture is filtered through diatomaceous earthand the filtrate evaporated to give 0.13 g of product as a light yellowsolid.

Reference Example 45 5-(4-Nitro-3-methylbenzoyl)-6,11-dihydro-5H-dibenzb,e!azepine

A mixture of 1.17 g of 6,11-dihydro-5H-dibenz b,e!azepine, 1.20 g of3-methyl-4-nitrobenzoyl chloride, 0.80 ml of diisopropylethylamine in 25ml of dichloromethane is stirred 18 hours at room temperature. Themixture is washed with water and dried (Na₂ SO₄). The solution isfiltered through a thin pad of hydrous magnesium silicate. The filtrateis concentrated and diluted while hot with hexane to give 1.40 g ofcrystals. Recrystallization from dichloromethane-hexane gives 1.26 g ofcrystals, m.p. 179°-180° C.

Reference Example 46 5-(4-Amino-3-Methylbenzoyl)-6,11-dihydro-5H-dibenzb,e!azepine

A mixture of 1.11 g of5-(4-nitro-3-methylbenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 50 ml ofethanol, 0.30 g of anhydrous hydrazine and 0.27 g palladium-on-carbon isrefluxed 1 hour, and then filtered through diatomaceous earth. Thefiltrate is evaporated and the residue recrystallized fromdichloromethane-hexane to give 0.80 g of crystals, m.p. 203°-204° C.

Reference Example 47 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-benzoic acid

A mixture of 0.975 g of 6,11-dihydro-5H-dibenz b,e!azepine and 0.20 g ofNaH (60% in oil) in 20 ml of tetrahydrofuran is stirred at roomtemperature for 0.5 hr. Then 1.1 g of mono-methyl terephthalyl chloride(prepared from mono-methyl terephthalate and thionyl chloride) is addedand the mixture refluxed 18 hours. The mixture is cooled, poured intoice water and filtered. The solid is triturated withdichloromethane-hexane to give 1.0 g of crystals, m.p. 182°-185° C. Thepreceding compound, methyl 4- (6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!benzoate (2.11 g), 20 ml of 2N NaOH and 20 mlof methanol is stirred overnight and then heated on a steam bath for 1hr. The solvent is removed to give a solid. The solid is extracted withether (discarded). The solid is dissolved in water and the solutionacidified with citric acid to give a solid. The solid is filtered andwashed with water to give 1.84 g of crystals, m.p. 220°-225° C.

Reference Example 48 2-Methylfurane-3-carbonyl chloride

A mixture of 4.0 g of methyl-2-methylfurane-3-carboxylate, 30 ml of 2NNaOH and 15 ml methanol is refluxed for 1.5 hours. The solvent isremoved under vacuum to give a solid. The solid is extracted withdichloromethane (discarded). The solid is dissolved in water and thesolution acidified with 2N citric acid to give a solid. The solid iswashed with water and dried to give crystals 1.05 g of crystals of2-methylfuran-3-carboxylic acid. The preceding compound (0.95 g) and 3ml of thionyl chloride is refluxed for 1 hr. The solvent is removed,toluene added (20 ml, three times) and the solvent removed to give theproduct as an oil.

Reference Example 49 2-Chloro-5-(4-nitrobenzoyl)-6,11-dihydro-5H-dibenzb,e!azepine

A mixture of 2.05 g of 2-chloro-6,11-dihydro-5H-dibenz b,e!azepine, 2.15g of 4-nitrobenzoyl chloride, 1.50 g of N,N-diisopropylethylamine, 54 mgof 4-(dimethylamino)pyridine in 15 ml of dichloromethane is refluxed for18 hours. The mixture is cooled and washed with H₂ O, 1N HCl, 1M NaHCO₃,brine and dried (Na₂ SO₄). The solution is filtered through a thin padof hydrous magnesium silicate and the pad washed with dichloromethane.The filtrate is concentrated and the residue recrystallized fromdichloromethane-hexane to give 2.33 g of crystals, m.p. 198°-201° C.

Reference Example 50 2-Chloro-5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenzb,e!azepine

A solution of 2.1 g of2-chloro-5-(4-nitrobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine in 400 mlof ethyl acetate-ethanol (1:1) and 0.25 g of palladium-on-carbon ishydrogenated in a Parr hydrogenator under 38 pounds per square inch ofhydrogen. The mixture is filtered through diatomaceous earth and thefiltrate concentrated to dryness. The solid (1.94 g) is dissolved indichloromethane and the solution filtered through a thin pad of hydrousmagnesium silicate. The filter pad is washed with dichloromethane andthe filtrate concentrated. The residue is crystallized fromdichloromethane-hexane to give 1.43 g of crystals, m.p. 211°-214° C.

Reference Example 511,2,3,4-Tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepine

To a solution of 5.0 g of 1,2,3,4-tetrahydro-5H-1-benzazepine and 5.91ml of triethylamine in 50 ml of dichloromethane, chilled in an ice bath,is added, dropwise, 6.32 g of 4-nitrobenzoyl chloride in 75 ml ofdichloromethane. The mixture is stirred at 0° C. for 1.5 hr and then atroom temperature for 18 hours. The mixture is washed with H₂ O, 2M HCl,1M NaOH and dried (Na₂ SO₄). The solvent is removed and the residuerecrystallized from ethanol with the aid of activated carbon to give7.75 g of light yellow crystals, m.p. 148.5°-150.5° C.

Reference Example 521,2,3,4-Tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzapin-5-one

A sample (3.0 g) of1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepine is dissolved in200 ml of tert-butanol (with heat). To the solution is added 8 ml of H₂O and 6.72 g of anhydrous MgSO₄ and then a solution of 3.36 g of KMnO₄in 100 ml of H₂ O is added and the mixture heated at 65° C. for 20hours. The mixture is filtered through diatomaceous earth and the filterpad washed with tert-butanol. The combined filtrate is concentrated(t-butanol removed) under vacuum. The solid is filtered and washed wellwith water to give (after drying) 2.7 g of crystals. Chromatography onsilica gel with hexane-ethyl acetate (2:1) gives 1.72 g of recoveredstarting material and 0.81 g of product as crystals, m.p. 135°-137° C.

Reference Example 53

3,4-Dihydro-1H-1-benzazepine-2,5-dione

To a solution of 225 ml of glacial acid and 8.5 ml of concentratedsulfuric acid is added 49.54 g (0.30 mol) of 2'-nitroacetophenone and47.02 g (0.50 mol) of glyoxylic acid (hydrated). The mixture is heatedat 100° C. 16 hours. The mixture is cooled and poured over crushed ice.After the ice melts, the mixture is filtered and the solid washed withcold water. The solid is dried and recrystallized fromdichloromethane-hexane to give 20.1 g of 3-(2-nitrobenzoyl)acrylic acidas white crystals, m.p. 153°-158° C. A solution of the precedingcompound (9.0 g) in 80 ml of ethanol and 1.6 g of palladium-on-carbon ishydrogenated in a Parr hydrogenator under 30 pounds per square inch ofhydrogen for 20 hours. The mixture is filtered through diatomaceousearth and the solvent is removed. The residue (7.0 g) is chromatographedon silica gel with hexane-ethyl acetate (1:1) as solvent to give 4.0 gof 3-(2-aminobenzoyl)acrylic acid as an orange solid, m.p. 103°-107° C.A 0.50 g sample of the preceding compound, 0.36 ml of triethylamine and0.43 ml of diethoxyphosphinyl cyanide in 20 ml of dichloromethane isstirred at room temperature for 5 days. The solvent is removed, ethylacetate is added and the mixture washed with water, 2N citric acid, 1MNaHCO₃, brine and dried (Na₂ SO₄). The solvent is removed and theresidue purified by chromatography over silica gel with ethylacetate-hexane (1:1) as solvent to give 0.190 g of light brown crystals,m.p. 168°-170° C.

Reference Example 54 4-(Dimethylamino)methylene!-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one

A mixture of 0.780 g of1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one and 10 ml oftert-butoxy bis(dimethylamino)methane (Bredereck's Reagent) is heated ona steam bath while stirring for 1.5 hours (solid dissolved). Coolinggives a solid and the mixture is diluted with ethyl acetate andfiltered. The solid is dissolved in dichloromethane-ethyl acetate (7:3)and the solution filtered through a thin pad of hydrous magnesiumsilicate. The filter pad is washed with dichloromethane-ethyl acetate(7:3) and the combined filtrate evaporated to give 0.43 g of yellowcrystals, Mass Spec (CI) MH⁺ =366, m.p. 180°-183° C.

Reference Example 55 6,7-Dihydro-7-(4-nitrobenzoyl)-5H-pyrimido 5,4-d!1!benzazepine

To a solution of 0.152 g (1.89 mmol) of formamidine hydrochloride in 10ml of methanol under argon is added 0.102 g (1.89 mmol) of sodiummethoxide. After stirring 5 min., a solution of 0.46 g (1.26 mmol) of 4-(dimethylamino)methylene!-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepine-5-onein 5 ml of methanol is added and the mixture stirred 18 hours. Thesolvent is removed, dichloromethane added, and the mixture filtered. Thesolid is washed with dichloromethane. The combined filtrate isconcentrated to dryness to give 0.47 g of tan foam. The preceding solidis purified by chromatography on silica gel. The compound is dissolvedin ethyl acetate-dichloromethane and applied to the column. The columnis then eluted with ethyl acetate to give 0.25 g of product as paleyellow crystals.

Reference Example 56 4-(Dimethylamino)methylene!-3,4-dihydro-1H-1-benzazepine-2,5-dione

A mixture of 0.250 g (1.43 mmol) of3,4-dihydro-1H-1-benzazepine-2,5-dione and 5.5 ml (4.93 g, 41.5 mmol) ofN,N-dimethylformamide, dimethylacetal is heated at 90° C. for 1.5 hour.The mixture is cooled, diluted with diethylether and filtered. The solidis washed well with diethylether and dried to give 0.26 g of tancrystals, m.p. 203°-205° C.

Reference Example 57 2-Methyl-6,7-dihydro-5H-pyrimido 5,4-d!1!benzazepine

To a solution of 0.308 g (3.26 mmol) of acetamidine hydrochloride in 15ml of methanol under argon is added 0.176 g of (3.26 mmol) of sodiummethoxide and the mixture stirred for 5 min. To the mixture is added0.50 g (2.17 mmol) of 4-(dimethylamino)methylene!-1,2,3,4-tetrahydro-5H-1-benzazepine-2,5-dioneand the mixture stirred at room temperature overnight. The mixture(containing thick precipitate) is diluted with 3 ml of methanol, chilledand filtered. The filtrate is concentrated to dryness. The residue andoriginal solid are combined and chloroform added. The mixture is washedwith water, the organic layer is treated with activated carbon and thenfiltered through a thin pad of hydrous magnesium silicate. The filtrateis evaporated to give 0.41 g of crystals, m.p. 257°-258° C.

The preceding compound is heated with 5 equivalents of lithium hydridein dioxane for 24 hours to give the product as a solid.

Reference Example 58 10,11-Dihydro-10-(4-nitrobenzoyl)dibenz b,f!1,4!-thiazepine

To a solution of 1.6 g of 10,11-dihydrodibenz b,f! 1,4!thiazepine in 30ml of dichloromethane is added 0.1 g of 4-(N,N-dimethylamino)pyridine, 4ml of triethylamine and 1.0 g of 4-nitrobenzoyl chloride and the mixtureis stirred for 16 hours. The mixture is poured into ice-water andextracted with 3×150 ml of dichloromethane. The combined organic extractis washed with water, 2N HCl, 2N Na₂ CO₃, water and dried (MgSO₄). Thesolvent is removed an vacuo and the product (2.6 g) purified bychromatography on silica gel with hexane-ethyl acetate (4:1) as eluentto give 2.2 g of crystals, m.p. 147°-149° C.

Reference Example 59 10,11-Dihydro-10-(4-aminobenzoyl)dibenz b,f!1,4!-thiazepine

A mixture of 2.2 g of 10,11-dihydro-10-(4-nitrobenzoyl)dibenz b,f!1,4!thiazepine in 150 ml of methanol is shaken in a Parr hydrogenatorunder 50 pounds per square inch of hydrogen for 72 hours. The mixture isfiltered through diatomaceous earth and the filtrate evaporated invacuo. The residue is recrystallized from chloroform-hexane to give 1.8g of crystals, m.p. 52°-55° C.

Reference Example 60 4- N-Methyl-N-(2-methylbenzoyl)amino!benzoic acid

A sample of 1.51 g of sodium hydride (60% in oil) is washed with hexaneunder argon to remove the oil. To the washed sodium hydride is added 5ml of N,N-dimethylformamide. To this mixture is added dropwise asolution of 8.69 g of ethyl 4- (2-methylbenzoyl)amino!benzoate in 20 mlof N,N-dimethylformamide. The mixture is stirred at room temperature for0.5 hour and then 5.23 g of methyl iodide is added. The mixture isstirred at room temperature for 16 hours. The mixture is diluted withwater and extracted with dichloromethane. The extract is dried (Na₂SO₄), concentrated to reduce the volume and the solution filteredthrough a thin pad of hydrous magnesium silicate. The filtrate isconcentrated in vacuo to give 11 g of an oil (1:1 mixture of product andN,N-dimethylformamide). The preceding product, ethyl 4-N-methyl-N-(2-methylbenzoyl)amino!benzoate, (11 g) is dissolved in 30 mlof methanol and 25 ml of 2N NaOH added. The mixture is refluxed for 2hours and the solvent removed. The residue is extracted with ether(discard) and the remaining residue dissolved in 50 ml of water. Thebasic solution is acidified with 2N citric acid and the solid filteredoff and washed with water. The product is air dried to give 6.72 g ofcrystals, m.p. 187°-190° C.

Reference Example 61 4- N-Methyl-N-(2-methylbenzoylamino!benzoylchloride

A solution of 6.72 g of 4- N-methyl-N-(2-methylbenzoyl)amino!benzoicacid in 20 ml of thionyl chloride is refluxed for one hour. Thevolatiles are removed in vacuo. Toluene is added to the residue and thenthe toluene removed in vacuo (repeated several times) to give the 7.3 gof product as a brown oil.

As described for Reference Example 60, but substituting the appropriateethyl 4- (N-aroyl)amino!-benzoate, the folowing compounds are prepared.

Reference Example 62 4- N-Methyl-N-(2-chlorobenzoyl)amino!benzoic acidReference Example 63 N- N-Methyl-N-(2,5-dichlorobenzoyl)amino!benzoicacid Reference Example 64 N- N-Methyl-N-2,4-dichlorobenzoyl)amino!-benzoic acid Reference Example 65 4-N-methyl-N-(2-chloro-4-methylbenzoyl)amino!-benzoic acid ReferenceExample 66 4- N-methyl-N-(2-methyl-4-chlorobenzoyl)amino!-benzoic acidReference Example 67 4- N-Methyl-N-(2,4-dimethylbenzoyl)amino!-benzoicacid Reference Example 68 4-N-Methyl-N-(2,3-dimethylbenzoyl)amino!-benzoic acid Reference Example 694- N-Methyl-N-(2-methoxybenzoyl)amino!benzoic acid Reference Example 704- N-Methyl-N-(2-trifluoromethoxybenzoyl)amino!-benzoic acid ReferenceExample 71 4- N-Methyl-N-(2,4-dimethoxybenzoyl)amino!-benzoic acidReference Example 72 4-N-Methyl-N-(2-methoxy-4-chlorobenzoyl)amino!-benzoic acid ReferenceExample 73 4- N-Methyl-N-(2-methylthiobenzoyl)amino!-benzoic acidReference Example 74 4-N-Methyl-N-(2-methylthiophen-3-ylcarbonyl)amino!-benzoic acid ReferenceExample 75 4- N-Methyl-N-(3-methylthiophen-2-ylcarbonyl)amino!-benzoicacid Reference Example 76 4-N-Methyl-N-(2-methylfuran-3-ylcarbonyl)amino!-benzoic acid ReferenceExample 77 4- N-Methyl-N-(3-methylfuran-2-ylcarbonyl!amino!-benzoic acidReference Example 78 4- N-Methyl-N-(phenylacetyl)amino!benzoic acidReference Example 79 4- N-Methyl-N-(2-chlorophenylacetyl)amino!-benzoicacid Reference Example 80 4-N-Methyl-N-(2-methoxyphenylacetyl)amino!-benzoic acid Reference Example81 4- N-Methyl-N-(2-methylphenylacetyl)amino!-benzoic acid ReferenceExample 82 4- N-Methyl-N-(cyclohexylcarbonyl)amino!-benzoic acidReference Example 83 4- N-Methyl-N-(3-cyclohexenecarbonyl)amino!-benzoicacid Reference Example 84 4- N-Methyl-N-(cyclohexylacetyl)amino!benzoicacid Reference Example 85 5,6-Dihydropyrido 2,3-b! 1,4!benzothiazepine

To a suspension of 11.67 g of 2-thiobenzoic acid in a mixture of 32 mlof ethanol and 11 ml of water is added portionwise 12.72 g of solidsodium bicarbonate. After the complete addition, the mixture is stirredfor 15 minutes and 10.0 g of 2-chloro-3-nitropyridine added portionwise.The mixture is refluxed for 2 hours, cooled and then concentrated invacuo. The residual aqueous solution is diluted with 15 ml of water,acidified with 2N HCl and extracted twice with 250 ml of ethyl acetate.The extract is concentrated under vacuum to give a yellow solid residue.The residue is dissolved in a minimum of ethyl acetate by heating on asteam bath. The solution is cooled overnight and filtered. (2.5 g ofstarting material). The filtrate is concentrated, chilled and filteredto give 12.5 g of 2-(3-nitro-2-pyridinylthio)benzoic acid as a yellowsolid. The preceding compound (5.0 g) and 0.75 g of Pd/C in 60 ml ofethanol is shaken in a Parr hydrogenator under 45 psi of hydrogen for 18hours. The mixture is filtered through diatmoaceous earth and the filtercake washed with 200 ml of dichloromethane. The combined filtrate isevaporated in vacuo to give a solid. The solid is triturated withethanol and filtered to give 3.6 g of yellow solid. This solid (3.0 g)is again hydrogenated with Pd/c (0.50 g) in 50 ml of ethanol and 30 mlof acetic acid under 45 psi of hydrogen for 18 hours. The mixture isfiltered through diatomaceous earth and the filter cake washed withmethanol. The combined filtrate is concentrated in vacuo to give 1.6 gof solid. This solid in 25 ml of N,N-dimethylformamide is again reducedwith 0.80 g of Pd/C under 45 psi of hydrogen to give 0.57 g of solid.Recrystallization from ethyl acetate gives 0.28 g of2-(3-amino-2-pyridinylthio)benzoic acid. The preceding compound (0.20 g)is heated in 2-hydroxypyridine at 170° C. to give 5,6-dihydropyrido2,3-b! 1,4!benzothiazepine as a yellow solid. The preceding compound isreacted with borane-dimethylsulfide as described for Reference Example17 to give the product as a solid.

Reference Example 86 5,6-Dihydro-5-(4-aminobenzoyl)pyrido 2,3-b!1,4!-benzothiazepine

To a mixture of 10 mmol of 5,6-dihydropyrido- 2,3-b! 1,4!benzothiazepineand 11 mmol of 4-nitrobenzoyl in 25 ml of dichloromethane chilled to 0°C. is added 15 mmol of triethylamine. The mixture is stirred at roomtemperature for 5 hours and then diluted with 75 ml of dichloromethane.The mixture is washed with H₂ O, 2N citric acid, NaHCO₃, brine and dried(Na₂ SO₄). The solvent is removed to give5,6-dihydro-5-(4-nitrobenzoyl)pyrido 2,3-b! 1,4!benzothiazepine as asolid. A mixture of the preceding compound (5 mmol), 0.3 g of Pd/C and 3mmol of hydrazine in 25 ml of ethanol is refluxed for 3 hours. Themixture is filtered through diatomaceous earth and the filtrateevaporated in vacuo to give a solid. The solid is purified bychromatography on silica gel with ethyl acetate-hexane as solvent togive the product as a solid.

Reference Example 87 5,11-Dihydro-6-(4-aminobenzoyl)-6H-pyrido 2,3-e!1!-benzazepine

To a mixture of 10 mmol of 5,11-dihydro-6H-pyrido 2,3-e! 1!benzazepine,and 11 mmol of 4-nitrobenzoyl chloride in 25 ml of dichloromethane,chilled to 0° C., is added 15 mmol of triethylamine. The mixture isstirred at room temperature for 5 hours and diluted with 75 ml ofdichloromethane. The mixture is washed with H₂ O, 2N citric acid,NaHCO₃, brine and dried (Na₂ SO₄). The solvent is removed in vacuo togive 5,11-dihydro-6-(4-nitrobenzoyl)-6H-pyrido- 3,2-e! 1!benzazepine asa solid. A mixture of the preceding compound (5 mmol) 0.3 g of Pd/C and3 mmol of hydrazine in 25 ml of ethanol is refluxed 3 hours. The mixtureis filtered through diatomaceous earth and the filtrate evaporated invacuo to a solid. The solid is purified by chromatography on silica gelto give the product as a solid.

Reference Example 88 2-Nitro-2'-carboxy-diphenylamine

A stirred solid mixture of 13.7 g of anthranilic acid, 20.2 g ofo-bromonitrobenzene, 13.8 g of anhydrous potassium carbonate and 0.1 gof copper metal is heated 200° C. oil bath. The reaction mixture isheated for 2 hours, cooled and the solid washed with ether (3×100 ml).The solid is dissolved in hot water and filtered. The filtrate isacidified with 40 ml of HCl and the resulting solid is collected anddried to give 20.5 g of the desired product as a solid, m.p. 262°-265°C.

Reference Example 89 2-Amino-2'-carboxy-diphenylamine

A solution of 7.3 g of 2-nitro-2'-carboxy-diphenylamine in 50 ml ofmethanol containing 10% palladium-on-carbon is hydrogenated under 42pounds of pressure for 24 hours. The reaction mixture is filteredthrough diatomaceous earth. The filtrate is evaporated to dryness invacuo to give 6.6 g of the desired product as a solid, m.p. 72°-75° C.

Reference Example 90 5,11-Dihydro-10H-dibenz b,e! 1,4!diazepine-11-one

A mixture of 6.6 g of 2-amino-2'-carboxy-diphenylamine in 300 ml ofxylene is heated at reflux for 20 hours. The xylene is evaporated invacuo to a residue which is evaporated from 210 ml of toluene in vacuoto a residue which is evaporated from 50 ml of chloroform to give aresidue. The residue is dissolved in 10 ml of tetrahydrofuran and addedto 400 ml of ice-cold hexane. The resulting solid is collected, to give4.3 g of the desired product as a solid, m.p. 121°-123° C.

Reference Example 91 5,11-Dihydro-10H-dibenz b,e! 1,4!diazepine

To a stirred solution of 4.3 g of 5,11-dihydro-10H-dibenz b,e!1,4!diazepin-11-one in 50 ml of tetrahydrofuran, under nitrogen andcooled to 0° C. is added 4.0 ml of 10N methyl sulfide-borane complex.The ice bath is removed after 30 minutes and the reaction mixturestirred at room temperature for 18 hours. The reaction mixture is cooledin an ice bath and 30 ml of anhydrous methanol added dropwise andevaporated to dryness in vacuo. Another 30 ml of methanol is added andevaporated to a residue. The residue is quenched with 30 ml of 40%sodium hydroxide followed by heating at 110° C. for 45 minutes andcooling to room temperature. The reaction mixture is diluted with 200 mlof water and extracted with methylene chloride (3×100 ml). The combinedextracts are washed with 1N HCl, water and 0.5N NaOH. The organic layeris dried and evaporated in vacuo to give 3.2 g of the desired product,m.p. 114°-116° C.

Reference Example 92 5H-Dibenz b,e!azepine-6,11-dione

A mixture of 2.50 g of 2-aminobenzophenone-2'-carboxylic acid in 50 mlof xylene is stirred at reflux for 23 hours. The mixture is filtered togive 1.82 g of the desired product as a solid.

Reference Example 93 2-Chloro-5H-dibenz b,e!azepine-6,11-dione

A mixture of 1.0 g of 5H-dibenz b,e!azepine-6,11-dione in 50 ml ofacetic acid is stirred while chlorine is bubbled into the reactionmixture until saturated. The temperature increases to 38° C. Afterstanding, a precipitate forms and is filtered, washed with hexane andair dried to give 0.62 g of solid which is purified by chromatography togive the desired product as a solid, m.p. 289°-293° C.

Reference Example 94 2-Chloro-6,11-Dihydro-5H-dibenz b,e!azepine

To a mixture of 7.28 g of 2-chloro-5H-dibenz- b,e!azepine-6,11-dione in25 ml of anhydrous tetrahydrofuran, under argon, is added dropwise 8.5ml of (10M) boron-dimethyl sulfide. The reaction mixture is stirred atroom temperature for 18 hours. The reaction mixture is heated at refluxfor 3 hours and cooled to room temperature. While stirring, 25 ml ofmethyl alcohol is carefully added, followed by 100 ml of 2N NaOH. Thereaction mixture is heated at reflux for 24 hours and the solidcollected. The solid is dissolved in methylene chloride and washed with2N citric acid, water and dried (Na₂ SO₄). The volatiles are evaporatedin vacuo to give 4.16 g of a residue which is crystallized from ethylacetate-hexane to give 2.05 g of the desired product as a crystallinesolid, m.p. 137°-141° C.

Reference Example 95 5,6-Dihydro-6-(4-nitrobenzoyl)-4H-isoxazolo 4,5-d!-1!benzazepine

A solution of 0.250 g of 1,2,3,4-tetrahydro-4-(dimethylamino)methylene-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one and95.2 mg of hydroxylamine hydrochloride in 8 ml of methyl alcohol isheated at reflux under argon for 4 hours. The methanol is evaporated invacuo to a residue which is dissolved in 10% ethyl acetate in methylenechloride and the solution passed through a pad of silica gel. Thefiltrate is evaporated in vacuo to give the desired product as a solid.CIMS:MH⁺ =336.

Reference Example 96 5,6-Dihydro-6-(4-aminobenzoyl)-4H-isoxazolo 4,5-d!-1!benzazepine

A mixture of 0.050 g of 5,6-dihydro-6-(4-nitrobenzoyl)-4H-isoxazolo4,5-d! 1!benzazepine and 0.169 g of SnCl₂ 2H₂ O in 2 ml of ethyl alcoholis heated at reflux under argon for 1 hour. Water and 10% NaHCO₃ isadded until basic. The volatiles are evaporated in vacuo to a residuewhich is stirred with 1:1 chloroform-methanol and filtered. The filtrateis evaporated in vacuo to a residue which is dissolved in methylalcohol, treated with activated carbon, filtered through diatomaceousearth and concentrated in vacuo to give 100 mg of the desired product asa white crystalline solid. CIMS(CH₄):MH⁺ =306.

Reference Example 976,7-Dihydro-2-methyl-7-(4-nitrobenzoyl)-5H-pyrimido- 5,4-d!1!benzazepine

To a stirred solution of 0.233 g of acetamidine hydrochloride in 36 mlof methyl alcohol under argon is added 0.133 g of NaOCH₃. After 5minutes, 0.600 g of 4-(dimethylamino)methylene!-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-oneis added and stirring continued for 18 hours. The volatiles areevaporated to a residue which is dissolved in ethyl acetate and passedthrough a pad of silica gel. The filtrate is evaporated in vacuo to give590 mg of the desired product as tan crystals, m.p. 211°-212° C. HRFABMS: Exact mass (M+H):361.1295.

Reference Example 986,7-Dihydro-2-methyl-7-(4-aminobenzoyl)-5H-pyrimido- 5,4-d!1!benzazepine

A mixture of 400 mg of6,7-dihydro-2-methyl-7-(4-nitrobenzoyl)-5H-pyrimido 5,4-d!1!benzazepine, 87 μl of anhydrous hydrazine and 40 mg of 10% Pd/C in 22ml of ethyl alcohol is heated at reflux for 1.25 hours, filtered throughdiatomaceous earth and the pad washed well with methyl alcohol. Thecombined filtrates are evaporated in vacuo to a residue which isdissolved in ethyl acetate and filtered through a pad of hydrousmagnesium silicate and the filtrate concentrated in vacuo to a residuewhich is dissolved in methyl alcohol and evaporated again to give 330 mgof the desired product as a yellow foam. HR FABMS: Exact mass (M+H):331.1555.

Reference Example 99 4-(Dimethylamino)methylene!-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one

A mixture of 1.35 g of1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one and 15 ml oftert-butoxy-bis(dimethylamino)methane is heated for on a steam bath for2 hours. The volatiles are evaporated in vacuo to a residue which isstirred with ether and filtered. The cake is washed with ether and thecombined filtrates evaporated in vacuo to a residue which is dissolvedin 30% ethyl acetate in methylene chloride and passed through a pad ofhydrous magnesium silicate. The filtrate is evaporated in vacuo to aresidue which is dissolved in 30% ethyl acetate in methylene chlorideand passed through a pad of hydrous magnesium silicate. The filtrate isevaporated in vacuo to a residue to give 1.60 g of yellow crystallineproduct, m.p. 180°-183° C.

Reference Example 1002,4,5,6-Tetrahydro-2-methyl-6-(4-nitrobenzoyl)-pyrazolo 4,3-d!1!benzazepin

A solution of 0.150 g of 4-(dimethylamino)-methylene!-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-oneand 44 μl of methylhydrazine in 5 ml of methyl alcohol is heated atreflux for 18 hours. A precipitate forms on standing. The volatiles areevaporated to a residue which is purified by column chromatography onsilica gel by elution with 5% ethyl acetate-methylene chloride. Theproduct fractions are combined and the volatiles evaporated to a residuewhich is dissolved in chloroform-methanol, filtered through glass wooland the filtrate evaporated in vacuo to give 0.110 g of the desiredproduct as pale yellow crystals.

Reference Example 1012,4,5,6-Tetrahydro-2-methyl-6-(4-aminobenzoyl)-pyrazolo 4,3-d!1!benzazepine

A mixture of 0.520 g of2,4,5,6-tetrahydro-2-methyl-6-(4-nitrobenzoyl)pyrazolo 4,3-d!1!benzazepine, 118 μl of anhydrous hydrazine and 52 mg of 10%palladium-on-carbon in 30 ml of absolute ethyl alcohol is heated atreflux for 1 hour. The reaction mixture is filtered through diatomaceousearth and the cake washed with 100 ml of methyl alcohol and 1:1chloroform-methyl alcohol to give 430 mg of the desired product asoff-white crystals. CIMS(CH₄)MH⁺ =319.

Reference Example 102 5-(2-Chloro-4-aminobenzoyl)-6,11-dihydro-5H-dibenzb,e!azepine

A mixture of 1.40 g of5-(2-chloro-4-nitrobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 0.20 gof 10% palladium-on-carbon, 0.25 g of anhydrous hydrazine in 25 ml ofabsolute ethanol is heated at reflux for 1 hour. The mixture is filteredthrough diatomaceous earth and the filtrate evaporated in vacuo to aresidue which is dissolved in methylene chloride and hexane added at theboil to give 0.60 g of the desired product as a crystalline solid, m.p.158°-161° C.

Reference Example 103 2- 2-(Tributylstannyl)-3-thienyl!-1,3-dioxolane

To a stirred solution of 15.6 g (0.10 mol) of2-(3-thienyl)-1,3-dioxolane in 100 ml of anhydrous ether,n-butyl-lithium (1.48N, in hexane, 74.3 ml) is added dropwise undernitrogen at room temperature. After being refluxed for 15 minutes, thereaction mixture is cooled to -78° C. and tri-n-butyltin chloride (34.18g, 0.105 mol) in 100 ml of dry tetrahydrofuran is added dropwise. Afterthe addition is complete, the mixture is warmed to room temperature andthe solvent evaporated. To the oily residue 100 ml of hexane is added,and the resulting precipitate (LiCl) is filtered off. The filtrate isevaporated and the residue distilled at reduced pressure, giving 34.16 g(77%) of the desired product.

Reference Example 104 2- 2-(2-Nitrophenyl)methyl!-3-thienyl!-1,3-dioxolane

A mixture of 2- 2-(tributylstannyl)-3-thienyl!-1,3-dioxolane (8.8 gms,20 mmols), 2-nitrobenzyl bromide (4.5 gms, 22 mmol) and tetrakis(triphenylphosphine)-palladium (0) (200 mg) is refluxed in degassedtoluene for 16 hours under nitrogen atmosphere. At the end, the reactionmixture is cooled to room temperature and filtered through diatomaceousearth. The toluene is removed by concentrating at reduced pressure andthe product isolated by silica gel column chromatography by elution with30% ethyl acetate:hexane to give 4.5 gms. of the desired product as aviscous liquid. Mass Spectrum; M⁺ 292.

Reference Example 105 4,10-Dihydro-5H-thieno 3,2-c! 1!benzazepine

A stirred solution of 4 gms of 2- 2-(2-nitrophenyl)methyl!-3-thienyl!-1,3-dioxolane in acetone (50 ml) andacetic acid (90% 50 ml) is heated to 60° C. Zinc dust (10 gms) is slowlyadded and after the addition, reaction mixture is stirred for 6 hours.At the end, reaction mixture is filtered and the residue washed withacetone and concentrated. The brown residue is extracted with chloroformand washed well with water. The organic layer is dried (Na₂ SO₄) andfiltered and concentrated. The product is isolated by silica gel columnchromatography by eluting with 20% ethyl acetate:hexane to give 2.0 g ofthe desired product as a pale yellow crystalline solid, m.p. 86° C. MassSpectrum; M⁺ 202.

Reference Example 106 4,5-Dihydro-4,4-dimethyl-2- 3-(2-nitrophenyl)methyl!-2-thienyl!oxazole

To a solution of 4,5-dihydro-4,4-dimethyl-2-(2-thienyl)-oxazole (4.5 gms25 mmol) in anhydrous ether at -70° C., n-butyl-lithium (2.5 molarsolution in hexane, 11 ml) is added drop by drop under N₂ atmosphere.The reaction mixture is stirred at -78° C. for 45 minutes andtri-n-butyltin chloride (8.3 gms 25 mmol) in dry ether is added drop bydrop. The reaction mixture is stirred at room temperature for 1 hour andquenched with water. The reaction mixture is extracted with ether,washed well with water, dried and concentrated. The product obtain ispure enough for further transformation. The oil product,4,5-dihydro-4,4-dimethyl-2- 3-(tributylstannyl)-2-thienyl!-oxazole ismixed with 2-nitrobenzyl bromide (5.5 g 25 mmol) in toluene and refluxedin the presence of tetrakis (triphenylphosphine)-palladium (0) (200 mg)for 16 hours. At the end, reaction mixture is cooled to room temperatureand filtered. Toluene is removed under reduced pressure and the productis isolated as brown oil by silica gel column chromatography by elutingit with 30% ethyl acetate:hexane to give 5.7 g of the desired product.Mass Spectrum; M⁺ 316.

Reference Example 107 9,10-Dihydro-4H-thieno 3,2-c! 1!benzazepin-10-one

A solution of 4,5-dihydro-4,4-dimethyl-2- 3-(2-nitrophenyl)methyl!-2-thienyl!oxazole 5 gms is refluxed inacetone/water (3:1 100 ml) containing 1N HCl (30 ml) for 24 hours. Thereaction mixture is concentrated and the residue is dissolved in glacialacetic acid (100 ml). The acetic acid is stirred at 70° C. and zinc dust(10 gm) is slowly added. Stirring is continued at 70° C. for 6 hours. Atthe end, the reaction mixture is cooled to room temperature andfiltered. Acetic acid is removed under reduced pressure and the residueis extracted with chloroform. The chloroform layer is dried andconcentrated to give 2.9 gms of the desired product as a brown solid.Mass Spectrum; M⁺ 215.

Reference Example 108 9,10-Dihydro-4H-thieno 3,2-c! 1!benzazepine

A stirred solution of 2.0 g of 9,10-dihydro-4H-thieno 2,3-c!1!benzazepin-10-one and lithium aluminum hydride (500 mg) intetrahydrofuran is refluxed for 4 hours. At the end, reaction mixture iscarefully quenched with ice cold water and extracted with chloroform.The organic layer is washed well with water and dried over anhydrous Na₂SO₄, filtered and concentrated. The product is purified by silica gelcolumn chromatography by eluting it with 30% ethyl acetate:hexane togive 1.2 g of the desired product as a bright yellow solid. MassSpectrum; M⁺ 202.

Reference Example 1094-Bromo-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one

A mixture of 0.200 g of1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one in 2.5 ml ofacetic acid is warmed until solution then allowed to cool to roomtemperature. While stirring, a solution of 0.103 g of bromine in 0.5 mlof acetic acid is added dropwise. After rapid decolorization, thereaction mixture is stirred for 1.5 hours and poured into water. Thesolid is collected, washed with water and air dried to give 220 mg ofthe desired product as a crystalline solid, Mass Spectrum; MH⁺ =389,391.

Reference Example 1105,6-Dihydro-2-methyl-6-(4-nitrobenzoyl)-4H-thiazolo 5,4-d! 1!benzazepine

A mixture of 1.19 g of4-bromo-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one and0.230 g of thioacetamide in 4 ml of ethyl alcohol is refluxed underargon for 18 hours. The volatiles are evaporated in vacuo to a residuewhich is partitioned between CHCl₃ and 10% NaHCO₃. The organic layer isseparated and washed twice with water. The organic layer is separated,dried (MgSO₄) and evaporated in vacuo to give 1.08 g of yellow foamwhich is purified by flash chromatography on silica by elution with 4%ethyl acetate in methylene chloride to give 560 mg of the desiredproduct as pale yellow foam.

Reference Example 1115,6-Dihydro-2-methyl-6-(4-aminobenzoyl)-4H-thiazolo 5,4-d! 1!benzazepine

A mixture of 0.080 g of5,6-dihydro-2-methyl-6-(4-aminobenzoyl)-4H-thiazolo 5,4-d! 1!benzazepineand 0.248 g of SnCl₂ dihydrate in 3.5 ml of ethyl alcohol is refluxedunder argon for 1 hour. The reaction mixture is diluted with ice waterand the pH adjusted to 8 with 10% NaHCO₃. After stirring for 3 hours,the mixture is extracted with CHCl₃ (3x). The combined organic layersare treated with activated carbon, filtered through a pad of MgSO₄ andthe filtrate evaporated in vacuo to a residue. The residue ischromatographed on silica gel by elution with 30% ethyl acetate inmethylene chloride to give 60 mg of the desired product as a tan solid,CIMS(CH₄):MH⁺ =336.

Reference Example 112 Methyl 4- 2-2-chlorophenyl!-2-cyano-2-(4-morpholinyl)ethyl!benzoate

A 0.876 g sample of 60% sodium hydride in oil is washed with hexanefollowed by the addition of 60 ml of dry N,N-dimethylformamide. Thereaction mixture is stirred for 1 hour under argon at room temperatureafter the addition of 4.73 g ofα-(2-chlorophenyl)-4-morpholineacetonitrile. To the reaction mixture isadded 4.58 g of methyl 4-(bromomethyl)benzoate and stirring continuedfor 3 hours. Several drops of acetic acid is added to ice water and thereaction quenched. The pH is 3-4 and saturated NaHCO₃ added to adjustthe pH to 6-7. Upon cooling a solid forms which is filtered, washed withwater and dried to give 5.92 g of yellow solid. Crystallization frommethylene chloride-hexane gives 2.10 g of the desired product as acrystalline solid, m.p. 116°-118° C.

Reference Example 113 Methyl 4- 2- 2-chlorophenyl)-2-oxoethyl!benzoate

A mixture of 1.0 g of methyl(4-(2-chlorophenyl)-2-cyano-2-(4-morpholinyl)ethyl!benzoate and 14 ml ofacetic acid and 6 ml of water is heated at reflux for 20 minutes thenpoured over crushed ice. After stirring for 15 minutes the resultingsolid is collected, washed with water and air dried to give 0.63 g oftan solid, m.p. 40°-42° C.

Reference Example 114 4- 2-(2-chlorophenyl)-2-oxoethyl!benzoic acid

A mixture of 18.78 g of methyl 4- 2-(2-chlorophenyl)-2-oxoethyl!benzoatein 288.8 ml of CH₃ OH, 72.2 ml of water and 5.2 g of NaOH is refluxedfor 3 hours then acidified with 2N citric acid. The reaction mixture isevaporated in vacuo to remove the CH₃ OH. The aqueous phase is extractedwith CH₂ Cl₂ and acidified with 1N HCl. The resulting solid is collectedand dried under vacuum to give 17.27 g of the desired product, m.p.168°-172° C.

Example 1 N- 4- (10,11-dihydro-5H-dibenz b,f!azepin-5-yl)-carbonyl!phenyl!-2-methylbenzamide

To a mixture of 1.37 g (5 mmol) of 4- (2-methylbenzoyl)amino!benzoylchloride and 0.061 g of 4-(dimethylamino)pyridine in 4 ml of pyridine isadded 0.975 g (5 mmol) of 10,11-dihydro-5H-dibenz b,f!azepine. Themixture is heated at 80° C. for 18 hours and then 0.2 g of sodiumhydride (60% in oil) (5 mmol) is added. The mixture is refluxed for 2hours, diluted with dichloromethane and water and then filtered. To thefiltrate is added 1N HCl and the mixture filtered. The filtrate is dried(Na₂ SO₄) and the solvent removed to give a solid. The solid (1.1 g) ischromatographed on thick layer silica gel plates to give 70 mg of yellowsolid, m.p. 112°-118° C. Anal. Calc'd for C₂₉ H₂₄ N₂ O: C,80.5; H,5.6;N,6.5. Found: C,78.7; H,5.8; N,6.7.

Example 2 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-2-methylbenzamide

To a solution of 0.27 g (1 mmol) of 4- (2-methylbenzoyl)amino!benzoylchloride in 2 ml of tetrahydrofuran is added 0.20 g (1 mmol) of6,11-dihydro-5H-dibenz b,e!azepine and 0.20 g of triethylamine. Themixture is stirred at room temperature for 3 hours and the solventremoved under vacuum. To the residue is added 1N HCl and the mixtureextracted with ethyl acetate (20 ml) and the extract washed withsaturated NaHCO₃, brine and dried (Na₂ SO₄). The solution is filteredthrough a thin pad of hydrous magnesium silicate and the filtrateevaporated. The residue is triturated with ether-hexane and filtered togive 0.47 g of a white solid: Mass Spectrum; EI 433 (M+1); EI-highresolution 432.1842. Anal. Calc'd for C₂₉ H₂₄ N₂ O₂ : C,80.5; H,5.6;N,6.5. Found: C,79.0; H,6.0; N,6.1. A sample crystallized from ethylacetate-hexane gives crystals, m.p. 198°-203° C.

Example 3 3-Methyl-N- 4-(5(6H)-phenanthridinyl)carbonyl!-phenyl!-2-thiophenecarboxamide

To 0.193 g (1.2 mmol) of 3-methylthiophene-2-carbonyl chloride in 3 mlof dichloromethane, cooled to 0° C., is added 209 μl of triethylamine.The mixture is stirred and 0.30 g (1 mmol) of5-(4-aminobenzoyl)-5,6-dihydrophenanthridine is added. The mixture isstirred at room temperature overnight and then concentrated undervacuum. To the residue is added 30 ml of ethyl acetate and the mixturewashed with 2 ml each of water, 2N citric acid, LM sodium bicarbonateand brine. The organic layer is dried (Na₂ SO₄) and the solvent removedto give 0.30 g of solid. The solid is chromatographed on thick layersilica gel plates with ethyl acetate-hexane (1:1) as solvent to give 150mg of product as a yellow foam. Anal. Calc'd for C₂₆ H₂₀ N₂ O₂ S:C,71.3; H,6.0; N,6.9; S,7.9. Found: C,71.0; H,5.8; N,6.8; S,7.8.

Example 4 N- 4- (2-Chlorodibenz b,f!1,4!oxazepin-10(11H)-yl)-carbonyl!phenyl!-2-methylbenzamide

To a mixture of 0.229 g (1.0 mmol) of 2-chloro-10,11-dihydrodibenz b,f!1,4!oxazepine in 1.0 ml of pyridine under nitrogen is added 0.30 g (1.1mmol) of 4- (2-methylbenzoyl)amino!benzoyl chloride. The mixture isstirred at room temperature for 1 hour, heated on a steam bath for 5minutes and 8 ml of 2N HCl added. The mixture is extracted with ethylacetate and the extract washed three times with 1 ml of 1N sodiumbicarbonate. The organic layer is dried (MgSO₄) and the solvent removed.The residue is crystallized from ethyl acetate-hexane to give 0.24 g ofcrystals, m.p. 207°-208° C. Anal. Calc'd for C₂₈ H₂ N₂ O₃ Cl: C,71.9;H,4.5; N,6.0; Cl,7.6. Found: C,71.6; H,4.6; N,5.9; Cl,7.4.

Example 5 2-Methyl-N- 4-(5(6H)-phenanthridinyl)carbonyl!-phenyl!benzamide

To a solution of 0.181 g (1.0 mmol) of 5,6-dihydrophenanthridine in 2 mlof warm pyridine is added 0.273 g (1.0 mmol) of 4-(2-methylbenzoyl)amino!-benzoyl chloride. The mixture is stirredovernight at room temperature, 1.2 ml of 2N HCl added. The solid whichseparates is filtered and washed with water. The solid is dissolved indichloromethane and the solution washed with 2M sodium carbonate. Theorganic layer is concentrated and the residue chromatographed twice onsilica gel with ethyl acetate-hexane as solvent to give 79 mg ofcrystals, m.p. 190°-194° C. Mass Spec-FAB 419 (M+R). Anal. Calc'd forC₂₈ H₂₀ N₂ O₂ H₂ O: C,77.4; H,5.1; N,6.4. Found: C,77.5; H,5.1; N,6.4.

Example 6 N- 4- (11,12-Dihydrodibenzb,f!azocin-5-(6H)-yl)-carbonyl!phenyl!-2-methylbenzamide

To a mixture of 0.245 g (1 mmol) of 5,6,11,12-tetrahydrodibenzb,f!azocine hydrochloride and 30 μl (2.2 mmol) of triethylamine in 2 mlof dichloromethane is added a solution of 0.281 g (1.1 mmol) of 4-(2-methylbenzoyl)amino!benzoyl chloride in 4 ml of dichloromethane. Themixture is stirred overnight at room temperature, washed with water 2NHCl (3×2 ml) and 1N sodium bicarbonate (3×2 ml). The organic layer isdried (MgSO₄) and filtered through a thin pad of hydrous magnesiumsilicate (pad washed with 3 volumes of CH₂ Cl₂). The filtrate isconcentrated to give 200 mg of a foam; Mass Spec.-FAB 447 (M+H). Anal.Calc'd for C₃₀ H₂₆ N₂ O₂ : C,80.7; H,5.9; N,6.3. Found: C,79.1; H,5.7;N,6.1.

Example 7 2,6-Dichloro-N- 4-(5(6H)-phenanthridinyl)carbonyl!-phenyl!benzamide

A mixture of 300 mg (0.5 mmol) of5-(4-aminobenzoyl)-5,6-dihydrophenanthridine and 230 mg of (0.55 mmol)of 2,6-dichlorobenzoyl chloride in 1.2 ml of pyridine is heated (100°C.) for 3 hr and then stirred at room temperature for 6 days. To themixture is added 10 mg of 4-(dimethylamino)pyridine and the mixturestirred for 22 days. To the mixture is added 6 ml of 2N HCl and thesolid filtered and washed with 2N HCl, 1N NaOH, H₂ O to give 0.57 g ofsolid. The solid is chromatographed on thick layer silica gel plateswith hexane ethyl-acetate (1:1) to give 110 mg of solid.Recrystallization from CH₂ Cl₂ -diisopropyl ether to give 73 mg of whitecrystals, m.p. 230°-235° C. Anal. Calc'd for C₂₇ H₁₈ Cl₂ N₂ O₂ H₂ O:C,66.0; H,4.1; N,5.7; Cl,14.4. Found: C,65.5; H,4.1; N,5.6; Cl,14.6.

Example 8 3,4-Dichloro-N- 4-(5(6H)-phenanthridinyl)carbonyl!-phenyl!benzamide

A mixture of 150 mg (0.5 mmol) of5-(4-aminobenzoyl)-5,6-dihydrophenanthridine and 115 mg (0.55 mmol) of3,4-dichlorobenzoyl chloride in 1 ml of pyridine is stirred at roomtemperature for 6 hours. To the mixture is added 6 ml of 2N HCl and themixture stirred and filtered to give a solid. The solid is washed withwater, 2N sodium carbonate and water to give 254 mg of crystals, m.p.94°-95° C. The solid is chromatographed on thick layer silica gel plateswith hexane ethyl-acetate (1:1) as solvent to give 107 mg of solid. MassSpec (FAB) 473 (M+H).

Example 9 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-2,5-dichlorobenzamide

A mixture of 0.625 g (2 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 0.629 g (3 mmol)of 2,5-dichlorobenzoyl chloride, 0.303 g (3 mmol) of triethylamine and15 mg of 4-(dimethylamino)pyridine in 10 ml of dichloromethane isstirred at room temperature for 3 hours. The mixture is washed withwater, 1N HCl, H₂ O, 1M NaHCO₃, brine and dried (Na₂ SO₄). The solventis removed to give crystals. Recrystallization from hexane-CH₂ Cl₂ gives0.16 g of white crystals, m.p. 203°-231° C. Anal. Calc'd for C₂₈ H₂₀ Cl₂N₂ O₂ : C,69.0; H,4.1; N,5.8; Cl,14.6. Found: C,69.0; H,3.8; N,5.6;Cl,14.8.

Example 10 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-2,4-dichlorobenzamide

As described for Example 9, 0.111 g (1.1 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz- b,e!azepine in 8 ml ofdichloromethane is reacted with 0.230 g of (1.1 mmol) of2,4-dichlorobenzoyl chloride. The product is recrystallized fromhexane-dichloromethane to give 0.24 g of crystals, m.p. 212°-215° C.Anal. Calc'd for C₁₈ H₂₀ Cl₂ N₂ O₂ H₂ O: C,66.5; H,4.4; N,5.5. Found:C,66.8; H,4.0; N,5.5.

Example 11 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-2,3-dimethylbenzamide

As described for Example 9, 0.628 g (2 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine is reacted with0.506 g (3.0 mmol) of 2,3-dimethylbenzoyl chloride in dichloromethane.The product is recrystallized from hexane-dichloromethane to give 0.12 gof crystals, m.p. 138°-142° C. Anal. Calc'd for C₃₀ H₂₆ N₂ O₂ : C,80.7;H,5.9; N,6.3. Found: C,80.0; H,5.9; N,6.1.

Example 12 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-2,5-dimethylbenzamide

As described for Example 9, 0.471 g (1.5 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz- b,e!azepine is reacted with0.303 g (1.8 mmol) of 2,5-dimethylbenzoyl chloride in 10 ml ofdichloromethane. The product is recrystallized fromdichloromethane-hexane to give 0.43 g of crystals, m.p. 213°-216° C.Anal. Calc'd for C₃₀ H₂₆ N₂ O₂ : C,80.7; H,5.9; N,6.3. Found: C,80.0;H,5.9; N,6.1.

Example 13 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-2,4-dimethylbenzamide

As described in Example 9, 0.471 g (1.5 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine is reacted with0.303 g (1.8 mmol) of 2,4-dimethylbenzoyl chloride in 10 ml ofdichloromethane. The product is recrystallized fromhexane-dichloromethane to give 0.38 g of crystals, m.p. 197°-199° C.Anal. Calc'd for C₃₀ H₂₆ N₂ O₂ 1/2 H₂ O: C,79.1; H,6.0; N,6.2. Found:C,79.0; H,5.8; N,6.2.

Example 14 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-2-chlorobenzamide

As described in Example 9, 0.471 g (1.5 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine is reacted with0.315 g (1.8 mmol) of 2-chlorobenzoyl chloride in dichloromethane. Theproduct is chromatographed on thick layer silica gel plates withhexane-ethyl acetate (1:1) as solvent to give a solid. Recrystallizationfrom hexane-dichloromethane gives 100 mg of crystals, m.p. 110°-115° C.Anal. Calc'd for C₂₈ H₂₁ ClN₂ O₂ 1/2 H₂ O: C,72.8; H,4.8; N,6.1; Cl,7.7.Found: C,72.6; H,4.5; N,5.8; Cl,8.7.

Example 15 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-2-methylbenzamide

As described for Example 9, 0.942 g (3 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine is reacted with0.52 g (3.3 mmol) of 2-methylbenzoyl chloride in 20 ml ofdichloromethane. The product is triturated with hexane-ethyl acetate togive 1.0 g of yellow crystals, m.p. 198°-203° C.

Example 16 2-Chloro-N- 4- (6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!benzeneacetamide

A mixture of 0.471 g (1.5 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 0.340 g (1.8mmol) of 2-chlorophenylacetyl chloride, 0.20 g of triethylamine and 9 mgof 4-(dimethylamino)-pyridine in 10 ml of dichloromethane is stirred atroom temperature for 48 hours. An additional 0.27 g of2-chlorophenylacetyl chloride is added and the mixture stirred at roomtemperature for 2.5 hr. The mixture is washed with 1N HCl, H₂ O, 1MNaHCO₃, brine and dried (Na₂ SO₄). The solvent is removed and the solidrecrystallized from dichloromethane to give 0.27 g of crystals, m.p.191°-194° C. Anal. Calc'd for C₂₉ H₂₃ ClN₂ O₂ : C,74.6; H,5.0; N,6.0;Cl,7.6. Found: C,74.4; H,4.9; N,5.9; Cl,7.8.

Example 17 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-3-pyridinecarboxamide

A mixture of 0.628 g (2 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 0.551 g (3 mmol)of nicotinoyl chloride, hydrochloride, 0.606 g (6 mmol) of triethylamineand 15 mg of 4-(dimethylamino)-pyridine in 17 ml of dichloromethane isrefluxed for 7 hours. The mixture is washed with H₂ O, 2N citric acid,H₂ O, 1N NaHCO₃, brine and dried (Na₂ SO₄). The solvent is removed andthe solid recrystallized from hexane-dichloromethane to give 0.12 g ofcrystals, m.p. 217°-220° C. Anal Calc'd for C₂₇ H₂₁ N₃ O₂ H₂ O: C,74.1;H,5.3; N,9.6. Found: 73.6; H,4.7; N,9.8.

Example 18 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-3-methyl-2-thiophenecarboxamide

As described for Example 9, 0.314 g (1 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine is reacted with0.177 g (1.1 mmol) of 3-methyl-2-thiophenecarbonyl chloride in 5 ml ofdichloromethane and 0.111 g of triethylamine for 2 hours at roomtemperature to give crystals. Recrystallization fromdichloromethane-hexane gives 0.235 g of crystals, m.p. 201°-204° C.

Example 19 N- 4- (6,11-Dihydro-5H-dibenz b,e!azepine-5-yl)-carbonyl!phenyl!-3-(trifluoromethyl)benzamide

As described for Example 9, 0.314 g (1 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine is reacted with0.302 g (1.4 mmol) of 3-(trifluoromethyl)benzoyl chloride in 9 ml and0.145 g (1.4 mmol) of triethylamine for 1.5 hour at room temperature.The product is recrystallized from ethyl acetate-hexane to give 0.14 gof crystals, m.p. 190°-191° C.

Example 20 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-4-(trifluoromethyl)benzamide

As described for Example 9, 0.314 g of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine is reacted with0.269 g (1.29 mmol) of 4-trifluoromethylbenzoyl chloride and 0.130 g(1.29 mmol) of triethylamine in 9 ml of dichloromethane for 1.5 hours atroom temperature. The product is triturated with ethyl acetate-hexane togive 0.43 g of crystals, m.p. 205°-207° C.

Example 21 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-2,4-difluorobenzamide

As described for Example 9, 0.314 g (1.0 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz- b,e!azepine is reacted with0.194 g (1.1 mmol) of 2,4-difluorobenzoyl chloride and 0.111 g (1.1mmol) of triethylamine in 10 ml of dichloromethane for 1.5 hours at roomtemperature. The product is recrystallized from ethyl acetate-hexane togive 0.37 g of crystals, m.p. 215°-217° C.

Example 22 N- 4- 6,11-Dihydro-11-methyl-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methylbenzamide

A sample of 6,11-dihydro-11-methyl-5H-dibenz- b,e!azepine is synthesizedas described in J. Chem. Soc. Perkin I, 1279 (1976). A 0.210 g (1 mmol)sample is added to a stirred and cooled mixture of 0.328 g (1.2 mol) of4- (2-methylbenzoyl)amino!benzoyl chloride, 279 mL (2.0 mmol) oftriethylamine and 26 mg of 4-(dimethylamino)pyridine in 4 ml ofdichloromethane. The solution is stirred at room temperature overnight.An additional 0.328 g of 4- (2-methylbenzoyl)amino!benzoyl chloride and150 μl of triethylamine is added and the mixture stirred at roomtemperature for 6 hours. The volatiles are removed and 30 ml of ethylacetate is added. The mixture is washed with 12 ml each of 2N citricacid, H₂ O, 1M NaHCO₃, brine and dried (Na₂ SO₄). The solvent is removedand the residue chromatographed on thick layer silica gel plates withhexane-ethyl acetate (2:1) as solvent to give 0.13 g of product as awhite solid. Anal. Calc'd for C₃₀ H₂₆ N₂ O₂ 1/4 H₂ O: C,79.9; H,5.9;N,6.2. Found: C,79.4; H,5.5; N,5.9.

Example 23 N- 4- 2- (Dimethylamino)sulfonyl!dibenz b,f!1,4!-oxazepin-10(11H)-yl!carbonyl!phenyl!-2-methylbenzamide

A solution of 0.22 g of10,11-dihydro-N,N-dimethyl-10-(4-nitrobenzoyl)dibenz b,f!1,4!oxazepine-2-sulfonamide, 50 mg of 10% Pd/C under an atmosphere of H₂is shaken in a Parr hydrogenator for 5 hours. The mixture is filteredthrough diatomaceous earth and the filter cake washed with ethylacetate. The filtrate is concentrated to 5a, 6 ml and 0.83 μl oftriethylamine added followed by the addition of 0.773 g of o-tolylchloride. The mixture is stirred overnight and then washed with H₂ O, 2NHCl, 1M Na₂ CO₃ and brine. The filtrate is filtered through a thin padof hydrous magnesium silicate and the pad washed with three volumes ofethyl acetate. The filtrate is concentrated under vacuum and theresidual oil chromatographed on thick layer silica gel plates withhexane-ethyl acetate (1:1) to give 83 mg of a foam. Mass Spectrum (FAB)540(M+H).

Example 24 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!benzamide

As described for Example 9, 0.314 g (1.0 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz- b,e!azepine is reacted with0.155 g (1.1 mmol) of benzoyl chloride and 0.111 g (1.1 mmol) oftriethylamine in 10 ml of dichloromethane for 1.5 hours at roomtemperature. The product is recrystallized from dichloromethane-hexaneto give 0.19 g of crystals, m.p. 219°-221° C. Anal. Calc'd for C₂₈ H₂₂N₂ O₂ : C,80.4; H,5.3; N,6.7. Found: C,79.6; H,5.5; N,6.7.

Example 25 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-2-(trifluoromethoxy)benzamide

As described for Example 9, 0.314 g (1.0 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz- b,e!azepine is reacted with0.247 g (1.1 mmol) of 2-(trifluoromethoxy)benzoyl chloride and 0.111 g(1.1 mmol) of triethylamine in 10 ml of dichloromethane at roomtemperature for 1.5 hours. The product is triturated withdichloromethane-hexane to give 0.35 g of crystals, m.p. 232°-235° C.

The following compounds are prepared as described for in Example 6.

Example 26 N- 4- (11,12-Dihydrodibenzb,f!azocin-5(6H)-yl)-carbonyl!phenyl!-2-chlorobenzamide Example 27 N- 4-(11,12-Dihydrodibenzb,f!azocin-5(6H)-yl)-carbonyl!phenyl!-2-fluorobenzamide Example 28 N- 4-(11,12-Dihydrodibenzb,f!azocin-5(6H)-yl)-carbonyl!phenyl!-2-methoxybenzamide Example 29 N-4- (11,12-Dihydrodibenzb,f!azocin-5(6H)-yl)-carbonyl!phenyl!-2,3-dimethylbenzamide Example 30N- 4- (11,12-Dihydrodibenzb,f!azocin-5(6H)-yl)-carbonyl!phenyl!-2,5-dimethylbenzamide Example 31N- 4- (11,12-Dihydrodibenzb,f!azocin-5(6H)-yl)-carbonyl!phenyl!-2,4-dichlorobenzamide Example 32N- 4- (11,12-Dihydrodibenzb,f!azocin-5(6H)-yl)-carbonyl!phenyl!-2,3-dichlorobenzamide Example 33N- 4- (11,12-Dihydrodibenzb,f!azocin-5(6H)-yl)-carbonyl!phenyl!-2-methyl-5-fluorobenzamide Example34 N- 4- (11,12-Dihydrodibenzb,f!azocin-5(6H)-yl)-carbonyl!phenyl!-2-chlorophenylacetamide

The following compounds are prepared as described in Example 3.

Example 35 N- 4-(5(6H)-Phenanthridinyl)carbonyl!phenyl!-2-chlorobenzamide Example 36 N-4- (5(6H)-Phenanthridinyl)carbonyl!phenyl!-2-fluorobenzamide Example 37N- 4- (5(6H)-Phenanthridinyl)carbonyl!phenyl!-2-methoxybenzamide Example38 N- 4- (5(6H)-Phenanthridinyl)carbonyl!phenyl!-2,3-dimethylbenzamideExample 39 N- 4-(5(6H)-Phenanthridinyl)carbonyl!phenyl!-2,5-dimethylbenzamide Example 40N- 4- (5(6H)-Phenanthridinyl)carbonyl!phenyl!-2,4-dichlorobenzamideExample 41 N- 4-(5(6H)-Phenanthridinyl)carbonyl!phenyl!-2,3-dichlorobenzamide Example 42N- 4- (5(6H)-Phenanthridinyl)carbonyl!phenyl!-2-methyl-5-fluorobenzamideExample 43 N- 4-(5(6H)-Phenanthridinyl)carbonyl!phenyl!-2-chlorophenylacetamide Example44 N- 4- (5(6H)-Phenanthridinyl)carbonyl!phenyl!-2-methylphenylacetamideExample 45 N- 4-(5(6H)-Phenanthridinyl)carbonyl!phenyl!-2-methyl-4-chlorobenzamideExample 46 N- 4-(5(6H)-Phenanthridinyl)carbonyl!phenyl!-2-chloro-4-methylbenzamideExample 47 N- 4-(5(6H)-Phenanthridinyl)carbonyl!phenyl!-2,6-dimethylbenzamide Example 48N- 4- (5(6H)-Phenanthridinyl)carbonyl!phenyl!-2-methylthio)benzamideExample 49 N- 4-(5(6H)-Phenanthridinyl)carbonyl!phenyl!-2-methyl-3-furanecarboxamide

The following compounds are prepared as described in Example 4.

Example 50 N- 4- (2-Chlorodibenz b,f!1,4!oxazepin-10(11H)-yl)-carbonyl!phenyl!-2-chlorobenzamide Example 51N- 4- (2-Chlorodibenz b,f!1,4!oxazepin-10(11H)-yl)-carbonyl!phenyl!-2-fluorobenzamide Example 52N- 4- (2-Chlorodibenz b,f!1,4!oxazepin-10(11H)-yl)-carbonyl!phenyl!-2-methoxybenzamide Example 53N- 4- (2-Chlorodibenz b,f!1,4!oxazepin-10(11H)-yl)-carbonyl!phenyl!-2,3-dimethylbenzamide Example54 N- 4- (2-Chlorodibenz b,f!1,4!oxazepin-10(11H)-yl)-carbonyl!phenyl!-2,5-dimethylbenzamide Example55 N- 4- (2-Chlorodibenz b,f!1,4!oxazepin-10(11H)-yl)-carbonyl!phenyl!-2,4-dichlorobenzamide Example56 N- 4- (Dibenz b,f!1,4!oxazepin-10(11H)-yl)-carbonyl!phenyl!-2,3-dichlorobenzamide Example57 N- 4- (Dibenz b,f!1,4!oxazepin-10(11H)-yl)-carbonyl!phenyl!-2-chlorophenylacetamideExample 58 N- 4- (Dibenz b,f!1,4!oxazepin-10(11H)-yl)-carbonyl!phenyl!-2-methyl-3-thiophenecarboxamideExample 59 N- 4- (Dibenz b,f!1,4!oxazepin-10(11H)-yl)-carbonyl!phenyl!-2-methylphenylacetamideExample 60 N- 4- (Dibenz b,f!1,4!oxazepin-10(11H)-yl)-carbonyl!phenyl!-2-methyl-4-chlorobenzamideExample 61 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-carbonyl!phenyl!-2-(methylthio)benzamide

As described for Example 9, a mixture of 0.242 g of2-(methylthio)benzoyl chloride (m.p. 61°-64° C.), 0.134 g oftriethylamine and 0.314 g of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenzb,e!azepine in 10 ml of dichloromethane is stirred for 2.5 hours andworked up to give a solid. Trituration with ethyl acetate-hexane gives0.150 g of crystals, m.p. 222°-225° C.

Example 62 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-methylbenzamide

As described for in Reference Example 12, a mixture of 3.3 g of10,11-dihydro-11-oxodibenz b,f! 1,4!thiazepine, 25 ml oftetrahydrofuran, 4.0 ml of 10 molar borane-dimethylsulfide (2.67equivalents) in tetrahydrofuran is stirred at room temperature 18 hoursto give, after work-up, 10,11-dihydrodibenz b,f! 1,4!thiazepine as whitecrystals, m.p. 145°-148° C. The preceding compound (3.5 g) is suspendedin 25 ml of dichloromethane and a solution of 1.8 g of 4-(2-methylbenzoyl)amino!benzoyl chloride in 50 ml of dichloromethaneadded. To the stirred mixture is added 4 ml of triethylamine and 0.2 gof 4-(dimethylamino) pyridine. The mixture is stirred at roomtemperature for 20 hours. The mixture is filtered and the filtrateconcentrated. The residue is purified by chromatography on silica gelwith hexane-chloroform-ethyl acetate (2:1:1) as solvent to give 2.2 g ofyellow crystals. A sample (0.80 g) is further purified by thick layerchromatography on silica gel with hexane-chloroform-ethyl acetate(2:1:1) as solvent to give 0.50 g of crystals, 76°-78° C.

The following compounds are prepared as described in Example 62.

Example 63 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-chlorobenzamide, m.p.116°-119° C. Example 64 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2,5-dichlorobenzamide Example65 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2,4-dichlorobenzamide, m.p.112°-115° C. Example 66 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-fluorobenzamide Example 67N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-chloro-4-methylbenzamideExample 68 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-methyl-4-chlorobenzamideExample 69 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2,4-dimethylbenzamide Example70 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2,3-dimethylbenzamide Example71 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-methoxybenzamide Example 72N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-(trifluoromethoxy)benzamideExample 73 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2,4-dimethoxybenzamide Example74 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2,6-dimethoxybenzamide Example75 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-benzamide Example 76 N- 4-(Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2,6-dichlorobenzamide Example77 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2,6-dimethylbenzamide Example78 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-methylthiobenzamide Example79 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-methyl-3-thiophenecarboxamideExample 80 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-3-methyl-2-thiophenecarboxamideExample 81 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-methyl-3-furanecarboxamideExample 82 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-3-methyl-2-furanecarboxamideExample 83 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-phenylacetamide Example 84 N-4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-chlorophenylacetamideExample 85 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-methylphenylacetamideExample 86 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-thiopheneacetamide Example87 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-furaneacetamide Example 88N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-phenyl!-2-methyl-3-thiopheneacetamideExample 89 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-3-chlorophenyl!-2-methylbenzamideExample 90 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!-2-methylphenyl!-2-methylbenzamideExample 91 N- 4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-methylbenzamide

As described for Example 2, 1 mmol of 4- (2-methylbenzoyl)amino!benzoylchloride, 1 mmol of 5H-dibenz b,d!azepine and 2 mmol of triethylamineare stirred at room temperature for 5 hours to give the product as apale yellow solid.

Example 92 N- 4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-methylbenzamide

A mixture of 0.10 g of 5-(4-aminobenzoyl)-6,7-dihydro-5H-dibenzb,d!azepine, 0.10 g of triethylamine in 1 ml of dichloromethane isstirred at room temperature for 6 hours. The mixture is diluted with 6ml of ethyl acetate and the solution washed with 1N HCl, 1N NaOH, brineand dried (Na₂ SO₄). The solvent is removed and the solid purified bychromatography on thick layer silica gel plates with the solvent ethylacetate-hexane (1:1) to give 90 mg of a pale yellow solid.

The following compounds are prepared as described in Example 92.

Example 93 N- 4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-chlorobenzamide Example 94 N- 4-(6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2,5-dichlorobenzamide Example 95 N- 4-(6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2,4-dichlorobenzamide Example 96 N- 4-(6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-fluorobenzamide Example 97 N- 4-(6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-chloro-4-methylbenzamide Example 98N- 4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-methyl-4-chlorobenzamide Example 99N- 4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2,4-dimethylbenzamide Example 100 N- 4-(6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2,3-dimethylbenzamide Example 101 N- 4-(6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-methoxybenzamide Example 102 N- 4-(6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-trifluoromethoxy)benzamide Example103 N- 4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2,4-dimethoxybenzamide Example 104 N-4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2,6-dimethoxybenzamide Example 105 N-4- (6,7-Dihydro-5H-dibenz b,d!azepin-5-yl)carbonyl!phenyl!benzamideExample 106 N- 4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2,6-dichlorobenzamide Example 107 N- 4-(6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2,6-dimethylbenzamide Example 108 N- 4-(6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl-2-methylthiobenzamide Example 109 N- 4-(6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-methyl-3-thiophenecarboxamide Example110 N- 4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-3-methyl-2-thiophenecarboxamide Example111 N- 4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-methyl-3-furanecarboxamide Example112 N- 4- (6,7-Dihydro-5-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-3-methyl-2-furanecarboxamide Example113 N- 4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!phenylacetamide Example 114 N- 4-(6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-chlorophenylacetamide Example 115 N-4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-methylphenylacetamide Example 116 N-4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!thiophene-2-carboxamide Example 117 N-4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-methyl-3-thiopheneacetamide Example118 N- 4- (6,7-Dihydro-5H-dibenzb,d!azepin-5-yl)carbonyl!phenyl!-2-methyl-3-furaneacetamide Example 119N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methyl-3-furanecarboxamide

As described for Example 9, 2-methyl-3-furanecarbonyl chloride isreacted with 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine togive the product. Recrystallization from dichloromethane-hexane givescrystals, m.p. 202°-204° C.

Example 120 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-3-chlorobenzo b!thiophene-2-carboxamide

As described for Example 9, 3-chlorobenzo b!-thiophene-2-carbonylchloride is reacted with 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenzb,e!azepine to give the product. Recrystallization fromdichloro-methane-hexane gives crystals, m.p. 252°-254° C.

N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-3-methylphenyl!-2-methylbenzamide

As described for Example 9, 2-methylbenzoyl chloride is reacted with5-(4-amino-3-methylbenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine to givethe product as crystals, m.p. 112°-114° C.

Example 122 6,11-Dihydro-5- 4-(2-methylphenyl)amino!carbonyl!-amino!benzoyl!-5H-dibenz b,e!azepine

A mixture of 0.314 g of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenzb,e!azepine and 0.173 g of o-tolylisocyanate in 15 ml of tetrahydrofuranis refluxed overnight. An additional 84 mg of o-tolylisocyanate is addedand the mixture refluxed for three hours. The solvent is removed, wateradded to the residue and the residue extracted with dichloromethane. Theextract is washed with 1N HCl, H₂ O, 1M NaHCO₃, brine and dried (Na₂SO₄). The solution is filtered through a thin pad of hydrous magnesiumsilicate. The pad is washed with dichloromethane. The filtrate (140 ml)is discarded. The filter pad is washed with acetone to give 0.370 g ofproduct. Trituration with dichloromethane-hexane gives 0.186 g ofcrystals, m.p. 188°-190° C.

Example 123 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-N-(2-methylphenyl)benzamide

To a mixture of 0.362 g of 4- (6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!benzoyl chloride and 0.101 g of triethylaminein 5 ml of dichloromethane is added a solution of 0.129 g of2-methylaniline in 3 ml of dichloromethane. The mixture is stirred 1.5hr at room temperature and then washed with H₂ O 1N HCl, 1M NaHCO₃,brine and dried (Na₂ SO₄). The solvent is removed to give a solid. Thesolid is dissolved in dichloromethane and filtered through a thin pad ofhydrous magnesium silicate with dichloromethane as eluent to give 0.025g of crystals, m.p. 214°-216° C.

Example 124 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-N-(2,3-dimethylphenyl)benzamide

As described for Example 123, a mixture of 0.361 g of 4-(6,11-dihydro-5H-dibenz b,e!azepin-5-yl)carbonyl!benzoyl chloride, 0.101g of triethylamine and 0.145 g of 2,3-dimethylaniline is stirred for 1.5hr. and worked up to give 0.44 g of crystals, m.p. 248°-251° C.

The following compounds are prepared as described in Example 123.

Example 125 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-N-(2-chlorophenyl!benzamide Example 126 4-(6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-N-(2,4-dichlorophenyl)benzamide Example 127 4-(6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-N-(2,5-dichlorophenyl)benzamide Example 128 4-(6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-N-(2,4-dimethylphenyl)benzamide Example 129 4-(6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-N-(2,5-dimethylphenyl)benzamide Example 130 4-(6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-N-(2-methoxyphenyl)benzamide Example 131 4-(6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-N-(2,4-dimethoxyphenyl)benzamide Example 1324- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-N-(3-chloro-4-methoxyphenyl)benzamide Example133 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-N-(5-chloro-2-methoxyphenyl)benzamide Example134 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-N-(3-chlorophenyl)benzamide Example 135 4-(6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-N-(2-chloro-5-methoxyphenyl)benzamide Example136 N- 4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl-2-methylbenzamide

A mixture of 0.349 g of2-chloro-5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 0.131 gof triethylamine and 0.201 g of 2-methylbenzoyl chloride in 13 ml ofdichloromethane is stirred at room temperature for 3 hours. The mixtureis poured into water and the organic layer separated. The organic layeris washed with 1N HCl, H₂ O, 1N NaHCO₃, brine and dried (Na₂ SO₄). Thesolution is filtered through a thin pad of hydrous magnesium silicateand the pad washed with dichloromethane. The filtrate is concentratedand the solid crystallized from dichloromethane-hexane to give 0.32 g ofcrystals, m.p. 187°-189° C.

Example 137 N- 4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!2,4-dichlorobenzamide

As described for Example 136, a mixture of 0.349 g of2-chloro-5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 0.131 gof triethylamine and 0.272 g of 2,4-dichlorobenzoyl chloride in 13 ml ofdichloromethane is stirred at room temperature for 3 hours. Work-upgives a solid which is crystallized from dichloromethane-hexane to give0.43 g of crystals, m.p. 199°-201° C.

Example 138 N- 4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!2,3-dimethylbenzamide

As described for Example 136, a mixture of 0.349 g of2-chloro-5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 0.131 gof triethylamine and 0.219 g of 2,3-dimethylbenzoyl chloride in 13 ml ofdichloromethane is stirred at room temperature for 18 hours. Work-upgives a solid which is recrystallized from dichloromethane-hexane togive 0.38 g of crystals 191°-193° C.

Example 139 2-Chloro-6,11-dihydro-5- 4-(2-methylphenyl)amino!-carbonyl!amino!benzoyl!-5H-dibenz b,e!azepine

As described for Example 122, a mixture of 0.348 g of2-chloro-5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine and 0.175g of o-tolylisocyanate in 15 ml of tetrahydrofuran is refluxed overnightand worked-up to give the product as a solid.

The following compounds are prepared as described in Example 136.

Example 140 N- 4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-chlorobenzamide Example 141 N- 4-(2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2,5-dichlorobenzamide Example 142 N- 4-(2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-chloro-4-methylbenzamide Example 143N- 4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methyl-4-chlorobenzamide Example 144N- 4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2,4-dimethylbenzamide Example 145 N- 4-(2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2,5-dimethylbenzamide Example 146 N- 4-(2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methoxybenzamide Example 147 N- 4-(2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-trifluoromethoxybenzamide Example 148N- 4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2,4-dimethoxybenzamide Example 149 N-4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2,6-dimethoxybenzamide Example 150 N-4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2,6-dichlorobenzamide Example 151 N- 4-(2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2,6-dimethylbenzamide Example 152 N- 4-(2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methylthiobenzamide Example 153 N- 4-(2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methylthiophene-3-carboxamide Example154 N- 4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-3-methylthiophene-2-carboxamide Example155 N- 4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methylfurane-3-carboxamide Example156 N- 4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-3-methylfurane-2-carboxamide Example157 N- 4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-chlorophenylacetamide Example 158 N-4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methylphenylacetamide Example 159 N-4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methoxy-4-chlorobenzamide Example 160N- 4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-trifluorobenzamide Example 161 N- 4-(2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methoxyphenylacetamide Example 162 N-4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!cyclohexylcarboxamide Example 163 N- 4-(2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl!carbonyl!phenyl!-3-cyclohexenecarboxamide Example 164 N-4- (2-Chloro-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!cyclohexylacetamide Example 165 N- 4-(6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methoxy-4-chlorobenzamide

As described for Example 9, a mixture of 0.377 g (1 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 0.295 g of2-methoxy-4-chlorobenzoyl chloride, and 0.15 g of triethylamine in 10 mlof dichloromethane is stirred at room temperature for 3 hours. Anadditional 0.148 g of 2-methoxy-4-chlorobenzoyl chloride and 75 mg oftriethylamine is added and the mixture stirred overnight. The solutionis worked-up as for Example 9 to give 0.38 g of product (crystallizedfrom dichloromethane-hexane) m.p. 237°-239° C.

Example 166 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-trifluoromethylbenzamide

As described for Example 9, a mixture of 0.377 g (1.44 mmol) of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 0.15 g oftriethylamine and 0.300 g (1.44 mmol) of 2-trifluoromethylbenzoylchloride is stirred at room temperature for 2 hours and then washed with1N HCl 1M NaHCO₃, brine and dried (Na₂ SO₄). The solution is passedthrough a thin pad of hydrous magnesium silicate and the filtrateevaporated to give a solid. Crystallization from dichloromethane-hexanegives 0.41 g of crystals, m.p. 191°-193° C.

Example 167 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-methylbenzamide

A mixture of 0.291 g of 6,11-dihydro-5H-dibenz b,e!azepine, 0.518 g of4- N-methyl-N-(2-methylbenzoyl)amino!benzoyl chloride and 0.182 g oftriethylamine in 10 ml of tetrahydrofuran is stirred at room temperaturefor 2 hours. The solvent is removed, the residue diluted with water andextracted with dichloromethane. The extract is washed with 1N HCl water,1M NaHCO₃, brine and dried (Na₂ SO₄). The solution is passed through athin pad of hydrous magnesium silicate. The filtrate is concentrated andchilled to give 0.52 g of crystals, m.p. 160°-170° C.

As described for Example 167, but substituting the appropriate aroylchloride, the following compounds are prepared.

Example 168 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-chlorobenzamide Example 169N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2,5-dichlorobenzamide Example170 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2,4-dichlorobenzamide Example171 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-fluorobenzamide Example 172N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-chloro-4-methylbenzamideExample 173 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-methyl-4-chlorobenzamideExample 174 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2,4-dimethylbenzamide Example175 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2,3-dimethylbenzamide Example176 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-methoxybenzamide Example 177N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-trifluoromethoxybenzamideExample 178 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2,4-dimethoxybenzamide Example179 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-methoxy-4-chlorobenzamideExample 180 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-3-methylthiobenzamide Example181 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-methylthiophene-3-carboxamideExample 182 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-3-methyl-2-thiophene-carboxamideExample 183 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-methyl-3-furane-carboxamideExample 184 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-3-methyl-2-furane-carboxamideExample 185 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methylphenylacetamide Example 186 N-4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-chlorophenylacetamideExample 187 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-methoxyphenylacetamideExample 188 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-methylphenylacetamideExample 189 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-methyl-3-thiopheneacetamideExample 190 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-2-trifluoromethylacetamideExample 191 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methylcyclohexanecarboxamide Example192 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-methyl-3-cyclohexanecarboxamideExample 193 N- 4- (5,6-Dihydro-7H-pyrimido 5,4-d!1!benzazepin-7-yl)carbonyl!phenyl!-2-methylbenzamide

As described for Example 1, 5 mmol of 4- (2-methylbenzoyl)amino!benzoylchloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido 5,4-d!1!benzazepine in pyridine to give the product as a solid.

Example 194 N- 4- (5,6-Dihydro-7H-pyrimido 5,4-d!1!benzazepin-7-yl)carbonyl!phenyl!-2,4-dichlorobenzamide

As described for Example 1, 5 mmol of 4-(2,4-dichlorobenzoyl)amino!benzoyl chloride is reacted with 5 mmol of5,6-dihydro-7H-pyrimido 5,4-d!- 1!benzazepine in pyridine to give theproduct as a solid.

Example 195 N- 4- (5,6-Dihydro-7H-pyrimido 5,4-d!1!benzazepin-7-yl)carbonyl!phenyl!-2,5-dichlorobenzamide

As described for Example 1, 5 mmol of 4-(2,5-dichlorobenzoyl)amino!benzoyl chloride is reacted with 5 mmol of5,6-dihydro-7H-pyrimido- 5,4-d! 1!benzazepine in pyridine to give theproduct as a solid.

Example 196 N- 4- (5,6-Dihydro-7H-pyrimido 5,4-d!1!benzazepin-7-yl)carbonyl!phenyl!-2-chlorobenzamide

As described for Example 1, 5 mmol of 4- (2-chlorobenzoyl)amino!benzoylchloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido 5,4-d!1!benzazepine in pyridine to give the product as a solid.

Example 197 N- 4- (5,6-Dihydro-7H-pyrimido 5,4-d!1!benzazepin-7-yl)carbonyl!phenyl!-2-chlorophenylacetamide Example 198N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2-methylbenzamide

A mixture of 5 mmol of 5,11-dihydro-6-(4-aminobenzoyl)-6H-pyrido 3,2-e!1!benzazepine, 5.5 mmol of 2-methylbenzoyl chloride and 10 mmol oftriethylamine in 15 ml of dichloromethane is stirred at room temperaturefor 16 hours. The mixture is diluted with 50 ml of dichloromethane andsolution washed with 20 ml each of H₂ O, 1M citric acid, NaHCO₃, brineand dried (Na₂ SO₄). The solvent is evaporated in vacuo to give a solid.The solid is purified by chromatography on silica gel to give theproduct as a solid.

The following compounds are prepared as described for in Example 198.

Example 199 N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2-chlorobenzamide Example 200 N- 4-(5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2,5-dichlorobenzamide Example 201 N-4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2,4-dichlorobenzamide Example 202 N-4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2-chloro-4-methylbenzamide Example203 N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2-methyl-4-chlorobenzamide Example204 N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2,4-dimethylbenzamide Example 205 N-4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2,3-dimethylbenzamide Example 206 N-4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2-methoxybenzamide Example 207 N- 4-(5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2-trifluoromethoxybenzamide Example208 N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2,4-dimethoxybenzamide Example 209 N-4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2-methoxy-4-chlorobenzamide Example210 N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-3-trifluoromethylbenzamide Example211 N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2-methylthiobenzamide Example 212 N-4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2-methyl-3-thiophenecarboxamideExample 213 N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-3-methyl-2-thiophenecarboxamideExample 214 N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2-methyl-3-furanecarboxamide Example215 N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-3-methyl-2-furanecarboxamide Example216 N- 4- (5,11-Dihydro-6H-pyrido 3,2-e! 1!benzazepin-6-yl)carbonyl!phenyl!-2-methoxyphenylacetamide Example 217N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2-chlorophenylacetamide Example 218N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2-methylphenylacetamide Example 219N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-2-methyl-3-thiopheneacetamide Example220 N- 4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!cyclohexanecarboxamide Example 221 N-4- (5,11-Dihydro-6H-pyrido 3,2-e!1!benzazepin-6-yl)carbonyl!phenyl!-3-cyclohexanecarboxamide Example 222N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-methylbenzamide

A mixture of 5 mmol of 5,6-dihydro-5-(4-aminobenzoyl)pyrido 2,3-b!1,4!benzothiazepine, 5.5 mmol of 2-methylbenzoyl chloride and 10 mmol oftriethylamine in 15 ml of dichloromethane is stirred at room temperaturefor 16 hours. The mixture is diluted with 50 ml of dichloromethane andthe solution washed with 20 ml each of H₂ O, 1M citric acid, NaHCO₃,brine and dried (Na₂ SO₄). The solvent is removed under vacuum to give asolid. The solid is purified by chromatography on silica gel with ethylacetate-hexane as solvent to give the product as a solid.

The following compounds are prepared as described for in Example 222.

Example 223 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-chlorobenzamide Example224 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2,5-dichlorobenzamideExample 225 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2,4-dichlorobenzamideExample 226 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-chloro-4-methylbenzamideExample 227 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-methyl-4-chlorobenzamideExample 228 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2,4-dimethylbenzamideExample 229 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2,3-dimethylbenzamideExample 230 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-methoxybenzamide Example231 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-trifluoromethoxybenzamideExample 232 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2,4-dimethoxybenzamideExample 233 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-methoxy-4-chlorobenzamideExample 234 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-trifluoromethylbenzamideExample 235 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-methylthiobenzamideExample 236 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-methyl-3-thiophenecarboxamideExample 237 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-3-methyl-2-thiophenecarboxamideExample 238 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-methyl-3-furanecarboxamideExample 239 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-3-methyl-2-furanecarboxamideExample 240 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!phenylacetamide Example 241N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-chlorophenylacetamideExample 242 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-methoxyphenylacetamideExample 243 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-methylphenylacetamideExample 244 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-2-methyl-3-thiopheneacetamideExample 245 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!cyclohexanecarboxamideExample 246 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!cyclopentanecarboxamideExample 247 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!cyclohexaneacetamide Example248 N- 4-(Pyrido 2,3-b!1,4!benzothiazepin-5(6H)-ylcarbonyl)phenyl!-3-cyclohexenecarboxamideExample 249 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2,3,5-trichlorobenzamide

A mixture of 366 mg of 2,3,5-trichlorobenzoyl chloride and 151 mg oftriethylamine in 2 ml of methylene chloride is stirred while 314 mg of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine in 5 ml ofmethylene chloride is added. Stirring is continued for 1.5 hours. Thereaction mixture is partitioned with water and the organic layer iswashed with 1N HCl, water, 0.5N NaOH and brine. The organic layer isdried with Na₂ SO₄ and passed through a pad of hydrous magnesiumsilicate. Hexane is added to the filtrate at the boil to give 0.52 g ofwhite solid residue which is purified by column chromatography on silicagel by elution with 2:1 hexane-ethyl acetate to give 120 mg of thedesired product as a crystalline solid, m.p. 225°-230° C.

Example 250 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-3,4-dichlorobenzamide

A mixture of 314 mg of 3,4-dichlorobenzoyl chloride and 151 mg oftriethylamine in 2 ml of methylene chloride is stirred while 314 mg of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine in 5 ml ofmethylene chloride is added. Stirring is continued for 2 hours. Thereaction mixture is partitioned with water and the organic layer iswashed 1N HCl, water, 0.5N NaOH and brine. The organic layer is driedwith Na₂ SO₄ and passed through a short pad of hydrous magnesiumsilicate. Hexane is added to the filtrate at the boil to give 0.35 g ofoff-white crystalline solid, m.p. 238°-241° C.

Example 251 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-3,5-dichlorobenzamide

A mixture of 301.6 mg of 3,5-dichlorobenzoyl chloride and 145 mg oftriethylamine is stirred in 2 ml of methylene chloride while 314 mg of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine in 5 ml ofmethylene chloride is added. The reaction mixture is stirred at roomtemperature for 2 hours and 100 mg of 3,5-dichlorobenzoyl chlorideadded. The reactants are heated at reflux for 36 hours. The cooledreaction mixture layer washed with 1N HCl, water, 1N NaOH, water andbrine. The organic layer is dried with Na₂ SO₄ and passed through ashort pad of hydrous magnesium silicate and hexane added to the filtrateat the boil to give 242 mg of the desired product as a crystallinesolid, m.p. 263°-265° C.

Example 252 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2,6-dichlorobenzamide

A mixture of 335 mg of 2,6-dichlorobenzoyl chloride and 258 mg ofN,N-diisopropylethylamine is stirred in 2 ml of xylene while 314 mg of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine is added. Thereactants are refluxed in an oil bath at 110° C. for 18 hours. Thexylene is evaporated in vacuo to a residue which is partitioned betweenmethylene chloride and water. The organic layer is separated, washedwith 1N HCl, 1M NaHCO₃, and brine. The organic layer is dried with Na₂SO₄ and passed through a pad of hydrous magnesium silicate. Hexane isadded to the filtrate at the boil to give 370 mg of the desired productas a crystalline solid, m.p. 257°-259° C.

Example 253 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2,3-dichlorobenzamide

A mixture of 301.6 mg of 2,3-dichlorobenzoyl chloride and 145 mg oftriethylamine is stirred while 314 mg of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz- b,e!azepine is added.Stirring is continued for 2 hours. Water is added and the organic layerwashed with 1N HCl, water, 1M NaHCO₃ and water then dried over Na₂ SO₄.The organic layer is passed through a pad of hydrous magnesium silicateand hexane added to the filtrate at the boil to give 0.32 g of thedesired product as a crystalline solid, m.p. 225°-230° C.

Example 254 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methyl-3-fluorobenzamide

A mixture of 248.5 mg of 1-methyl-2-fluoro-benzoyl chloride and 145 mgof triethylamine is stirred while 376.8 mg of5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine is added. Stirringis continued for 3 hours. Water is added and the organic layer washedwith 1N HCl, water, 1M NaHCO₃ and water then dried over Na₂ SO₄. Theorganic layer is passed through a pad of hydrous magnesium silicate. Thedesired product crystallizes from methylene chloride to give 0.417 g ofthe desired product, m.p. 167°-170° C.

Example 255 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-3-cyclohexene-1-carboxamide

A mixture of 208 mg of 3-cyclohexene-1-carbonyl chloride (prepared from3-cyclohexene-1-carboxylic acid and thionyl chloride) and 145 mg oftriethylamine in 3 ml of methylene chloride is added to a solution of377 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine in 7 mlof methylene chloride. The mixture is stirred for 18 hours, washed withwater, 1N HCl, water, 1M NaHCO₃ and brine then dried with Na₂ SO₄. Theorganic layer is passed through a short column of hydrous magnesiumsilicate and hexane added to the filtrate at the boil to give 340 mg ofthe desired product as a crystalline solid, m.p. 234°-236° C.

Example 256 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-3-chlorophenyl!-2,4-dichlorobenzamide

A mixture of 0.50 g of5-(2-chloro-4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 0.28 gof N,N-diisopropylethylamine and 0.45 g of 2,4-dichlorobenzoyl chloridein 25 ml of methylene chloride is Stirred at room temperature for 18hours. The reaction mixture is washed with water, saturated NaHCO₃,dried (Na₂ SO₄) and passed through a short pad of hydrous magnesiumsilicate. The filtrate is evaporated in vacuo to give the desiredproduct as a solid residue, m.p., 150°-165° C.

Example 257 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-2-methoxyphenyl!-2-methylbenzamide

A mixture of 1.0 g of5-(3-methoxy-4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 0.47 gof N,N-diisopropylethylamine and 0.56 g of 2-methylbenzoyl chloride in25 ml of methylene chloride is stirred at room temperature for 18 hours.The reaction mixture is washed with water and saturated NaHCO₃, dried(Na₂ SO₄) and passed through a short pad of hydrous magnesium silicate.Hexane is added at the boil to give 1.27 g of the desired product as acrystalline solid, m.p. 209°-210° C.

Example 258 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-2,6-dimethylphenyl!-2-methylbenzamide

A mixture of 1.42 g of 4- (benzoyl)amino!-3,5-dimethylbenzoic acid in 20ml of thionyl chloride is heated on a steam bath under argon for 1 hour.The volatiles are evaporated and the residue evaporated in vacuo fromtoluene to give 1.40 g of the desired product as a residue which isdissolved in 50 ml of methylene chloride and treated with 0.75 g ofN,N-diisopropylethylamine and 0.88 g of 10,11-dihydro-5H-dibenzb,e!azepine. The reactants are stirred at room temperature for 18 hoursand washed with water, saturated NaHCO₃, dried (Na₂ SO₄), passed througha pad of hydrous magnesium silicate and hexane added to the filtrate atthe boil to give 0.90 g of the desired product as a glass.

Example 259 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-2,6-dimethylphenyl!-2,4-dichlorobenzamide

A mixture of 1.69 g of 4-(2,4-dichlorobenzoyl)amino!-3,5-dimethylbenzoic acid in 2.0 ml ofthionyl chloride is heated on a steam bath under argon for 1 hour. Thevolatiles are evaporated and the residue evaporated in vacuo fromtoluene to give a residue. A solution of the residue in 25 ml ofmethylene chloride is treated with 0.75 g of N,N-diisopropylethylamineand 0.98 g of 10,11-dihydro-5H-dibenz b,e!azepine is stirred at roomtemperature for 18 hours. The reaction mixture is washed with saturatedNaHCO₃, dried (Na₂ SO₄) and passed through a pad of hydrous magnesiumsilicate. The filtrate is evaporated to a glass which is dissolved inmethylene chloride dried (Na₂ SO₄) and passed through a short pad ofhydrous magnesium silicate. The filtrate is evaporated to give 1.89 g ofthe desired product as an amorphorous solid.

Example 260 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-3-chlorophenyl!-2-methylbenzamide

A mixture of 0.31 g of5-(2-chloro-4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine and 0.15g of N,N-diisopropylethylamine in 10 ml of methylene chloride is cooledin an ice bath while 0.18 g of 2-methylbenzoyl chloride is added. Thebath is removed and the reactants stirred at room temperature for 18hours. The mixture is washed with water, 1N HCl, water, 1M NaHCO₃, brineand dried (Na₂ SO₄). The methylene chloride is removed in vacuo to give0.34 g of the desired product as crystalline solid, m.p. 138°-150° C. M⁺=467.

Example 261 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-2-methoxyphenyl!-2-methyl-5-fluorobenzamide

A mixture of 0.79 g of5-(3-methoxy-4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 0.40 gof N,N-diisopropylethylamine and 0.55 g of 2-methyl-5-fluorobenzoylchloride in 25 ml of methylene chloride is stirred at room temperaturefor 18 hours. The reaction mixture is washed with water and saturatedNaHCO₃, dried (Na₂ SO₄) and passed through a short pad of hydrousmagnesium silicate. Hexane is added at the boil to the filtrate to give1.05 g of the desired product as a solid.

Example 262 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-2-chlorophenyl!-2-methyl-3-fluorobenzamide

A mixture of 1.0 g of 6,11-dihydro-5H-dibenz b,e!azepine, 0.80 g ofN,N-diisopropylethylamine and 2.01 g of 4-(2-methyl-3-fluorobenzoyl)amino!-3-chlorobenzoyl chloride in 100 ml ofmethylene chloride is stirred at room temperature for 18 hours. Thereaction mixture is washed with water, saturated NaHCO₃, dried (Na₂ SO₄)and passed through a pad of hydrous magnesium silicate. Hexane is addedto the filtrate at the boil to give 1.79 g of the desired product as acrystalline solid, m.p. 254°-256° C.

Example 263 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-2-methoxyphenyl!-2,4-dichlorobenzamide

A mixture of 1.0 g of5-(3-methoxy-4-aminobenzoyl)-6,11-dihydro-5H-dibenz b,e!azepine, 0.47 gof N,N-diisopropylethylamine and 0.76 g of 2,4-dichlorobenzoyl chloridein 25 ml of methylene chloride is stirred at room temperature for 18hours. The reaction mixture is washed with water and saturated NaHCO₃,dried (Na₂ SO₄) and passed through a short pad of hydrous magnesiumsilicate. Hexane is added at the boil to give 1.39 g of the desiredproduct as a crystalline solid, m.p. 212°-214° C.

Example 264

N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-fluorobenzamide

A mixture of 1.85 g of 4-(2-methyl-3-fluorobenzoyl)amino!-2-chlorobenzoic acid in 30 ml ofthionyl chloride under argon is heated at reflux for 1 hour. The thionylchloride is evaporated in vauco to a residue which is stirred withhexane and collected to give 1.94 g of 4-(2-methyl-3-fluorobenzoyl)amino!-2-chlorobenzoyl chloride which isdissolved in 25 ml of methylene chloride and 0.49 g ofN,N-diisopropylethylamine added, followed by 0.65 g of6,11-dihydro-5H-dibenz b,e!azepine. The reactants are stirred at roomtemperature for 18 hours and washed with water, saturated NaHCO₃, dried(Na₂ SO₄) and passed through a short pad of hydrous magnesium silicateto give 1.19 g of the desired product as a glass.

Example 265 N- 4- (6,11-Dihydro-11-oxo-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methylbenzamide

A mixture of 1.08 g of N- 4- (6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methylbenzamide in 50 ml of t-butanolis heated, 2 ml of water is added followed by 1.18 g of MgSO₄, and 2.6 gof KMnO₄. An additional 0.84 g of KMnO₄ in 25 ml of water is addedfollowed by heating at 65° C. for 18 hours. The reaction mixture isfiltered and the filtrate evaporated in vacuo to give 1.2 g of a residuewhich is purified by column chromatography on silica gel by elution withethyl acetate and 9:1 ethyl acetate-methanol to give 160 mg of thedesired product as a solid, m.p. 115°-119° C.

Example 266 (2-Methylphenyl)methyl 4- (6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl)benzoate

To a mixture of 248 mg of 2-methylbenzyl alcohol in 4 ml of anhydroustetrahydrofuran is added 80 mg of sodium hydride (60% in mineral oil)and the mixture stirred for 1 hour. To the mixture is added 430 mg of 4-(6,11-dihydro-5H-dibenz b,e!azepin-5-yl)carbonyl!benzoyl chloride andthe mixture is stirred for 18 hours. The tetrahydrofuran is evaporatedin vacuo to a residue which is partitioned between methylene chlorideand water. The organic layer is separated and washed with 1N HCl, water,1M NaHCO₃, and brine. The organic layer is dried (Na₂ SO₄) and passedthrough a short pad of hydrous magnesium silicate and hexane added atthe boil to give 170 mg of the desired product, m.p. 140°-142° C.

Example 267 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-N-(dimethylamino)methyl!-2-methylbenzamide

To a suspension of 14 mg of 60% sodium hydride in oil, in 2 ml oftetrahydrofuran is added 0.13 g of N- 4- (6,11-dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-methylbenzamide. The reactants arestirred for 1 hour and 62 mg of N,N-dimethyl-methylene ammonium iodideadded followed by stirring for 2 hours. The mixture is diluted with 10ml of ether and filtered. The filtrate is evaporated in vacuo to aresidue which is stirred with hexanes to give 0.13 g of the desiredproduct as a white solid, m.p. 131°-133° C.

Example 268 N- 4- (5,11-dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-methylbenzamide

A mixture of 1.0 g of 5,11-dihydro-10H-dibenz b,e! 1,4!diazepine 1.9 gof 4- (2-methylbenzoyl) amino!benzoyl chloride, 4 ml of triethylamineand 0.2 g of 4-(dimethylamino)pyridine in 60 ml of methylene chloride isstirred at room temperature for 18 hours. The reaction mixture is pouredinto ice water and the separated organic layer washed with 50 ml each ofwater, 2N HCl, water, saturated NaHCO₃ and water. The organic layer isdried (Na₂ SO₄) and the solvent removed to give a residue. The residueis chromatographed on a silica gel column using 1:4 ethyl acetate-hexaneto give 1.8 g of the desired product as a solid, m.p. 68°-71° C.

The following compounds are prepared as described for Example 268.

Example 269 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-chlorobenzamide Example 270 N- 4-(5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2,4-dichlorobenzamide Example 271 N-4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2,5-dichlorobenzamide Example 272 N-4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-3,5-dichlorobenzamide Example 273 N-4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-fluorobenzamide Example 274 N- 4-(5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-3-fluorobenzamide Example 275 N- 4-(5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl!carbonyl!phenyl!-2-methyl-4-chlorobenzamide Example276 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2,3-dimethylbenzamide Example 277 N-4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-methoxybenzamide Example 278 N- 4-(5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-(trifluoromethoxy)benzamide Example279 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2,4-dimethoxybenzamide Example 280 N-4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2,6-dimethoxybenzamide Example 281 N-4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-methoxy-4-chlorobenzamide Example282 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-(trifluoromethyl)benzamide Example283 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-3-(trifluoromethyl)benzamide Example284 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2,6-dichlorobenzamide Example 285 N-4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-(methylthio)benzamide Example 286N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-4-fluoro-2-(trifluoromethyl)benzamideExample 287 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-4-fluoro-3-(trifluoromethyl)benzamideExample 288 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-fluoro-3-(trifluoromethyl)benzamideExample 289 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-3,5-dimethylbenzamide Example 290 N-4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2,3,5-trichlorobenzamide Example 300N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2,5-difluorobenzamide Example 301 N-4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-3-fluoro-2-methylbenzamide Example302 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2,3-dichlorobenzamide Example 303 N-4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-4-fluoro-2-methylbenzamide Example304 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-5-fluoro-2-methylbenzamide Example305 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl-2-fluoro-5-(trifluoromethyl)benzamideExample 306 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-fluoro-6-(trifluoromethyl)benzamideExample 307 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-3-fluoro-5-(trifluoromethyl)benzamideExample 308 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-methyl-3-thiophenecarboxamideExample 309 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-3-methyl-2-thiophenecarboxamideExample 310 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-methyl-3-furanecarboxamide Example311 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl!carbonyl!phenyl!-3-methyl-2-furanecarboxamide Example312 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-chlorobenzeneacetamide Example 313N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-methylbenzeneacetamide Example 314N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-methoxybenzeneacetamide Example 315N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-methyl-3-thiopheneacetamide Example316 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-3-methyl-2-thiopheneacetamide Example317 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!phenyl!-2-methyl-3-furaneacetamide Example318 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-2-methoxyphenyl!-3-fluoro-2-methylbenzamideExample 319 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-2-methoxyphenyl!-5-fluoro-2-methylbenzamideExample 320 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-2-methoxyphenyl!-2-chloro-4-fluorobenzamideExample 321 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-2-methoxyphenyl!-2,6-dichlorobenzamideExample 322 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-2-methoxyphenyl!-2-methylbenzamide Example323 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-2-methoxyphenyl!-2,5-dichlorobenzamideExample 324 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-chlorophenyl!-2-methylbenzamide Example325 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-chlorophenyl!-2-chlorobenzamide Example326 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-chlorophenyl!-2,3-dimethylbenzamideExample 327 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-chlorophenyl!-2,3-dichlorobenzamideExample 328 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-chlorophenyl!-2-chloro-4-fluoro-benzamideExample 329 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-chlorophenyl!-3-fluoro-2-methylbenzamideExample 330 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-chlorophenyl!-5-fluoro-2-methylbenzamideExample 331 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-chlorophenyl!-2,4-dichlorobenzamideExample 332 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-chlorophenyl!-4-fluoro-2-(trifluoromethyl)benzamideExample 333 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-chlorophenyl!-2-(methylthio)benzamideExample 334 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-chlorophenyl!-3-(trifluoromethoxy)benzamideExample 335 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-chlorophenyl!-2,6-dichlorobenzamideExample 336 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-chlorophenyl!-2-fluoro-6-trifluoromethyl)benzamide Example 337 N- 4- (5,11-Dihydro-10H-dibenzb,e! 1,4!diazepin-5-yl)carbonyl!-3-methylphenyl!-2,6-dichlorobenzamideExample 338 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-methylphenyl!-2-fluoro-6-(trifluoromethyl)benzamideExample 339 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-methylphenyl!-5-fluoro-2-methylbenzamideExample 340 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-methylphenyl!-2,4-dichlorobenzamideExample 341 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-methylphenyl!-4-fluoro-2-chlorobenzamideExample 342 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-methylphenyl!-3-fluoro-2-methylbenzamideExample 343 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-methylphenyl!-2,3-dimethylbenzamideExample 344 N- 4- (5,11-Dihydro-10H-dibenz b,e!1,4!diazepin-5-yl)carbonyl!-3-methylphenyl!-2-methylbenzamide Example345 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-2-methylbenzamide

A partial solution of 0.250 g of5,6-dihydro-6-(4-aminobenzoyl)-4H-isoxazolo 4,5-d! 1!benzazepine in 4 mlof tetrahydrofuran-dioxane (1:3) under argon is treated with 160 μl of2-methylbenzoyl chloride in 1.5 ml of dioxane followed by 114 μl oftriethylamine and stirring continued for 4.5 hours at room temperature.The volatiles are evaporated in vacuo to a residue which is dissolved inmethylene chloride containing methanol, washed with 10% NaHCO₃ andbrine, then treated with activated carbon. The mixture is filteredthrough MgSO₄ and the filtrate filtered through silica gel with 15%ethylacetate in methylene chloride. The filtrate is evaporated in vacuoto a residue which is dissolved in methylene chloride, filtered throughglass wool, evaporated to a residue which is dissolved in ethyl acetateby warming to give 0.25 g of the desired product as tan crystals, m.p.257°-260° C. HR FABMS: (M+H)=424.1657.

The following compounds are prepared as described in Example 345.

Example 346 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-2-methyl-4-chlorobenzamide Example347 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-2,3-dimethylbenzamide Example 348 N-4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-2-methoxybenzamide Example 349 N- 4-(4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-2-(trifluoromethoxy)benzamide Example350 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-2-(trifluoromethyl)benzamide Example351 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-2-(methylthio)benzamide Example 352N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-2,3-dichlorobenzamide Example 353 N-4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-3-fluoro-2-methylbenzamide Example354 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-5-fluoro-2-methylbenzamide Example355 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-2-chloro-4-fluorobenzamide Example356 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-4-fluoro-2-(trifluoromethyl)benzamideExample 357 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-4-fluoro-3-(trifluoromethyl)benzamideExample 358 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-4-fluoro-2-methylbenzamide Example359 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-2-fluoro-5-(trifluoromethyl)benzamideExample 360 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!phenyl!-2-fluoro-6-(trifluoromethyl)benzamideExample 361 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-3-fluoro-2-methylbenzamideExample 362 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methylbenzamide Example363 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2,3-dimethylbenzamideExample 364 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-5-fluoro-2-methylbenzamideExample 365 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-chloro-4-fluorobenzamideExample 366 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2,3-dichlorobenzamideExample 367 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-methylphenyl!-2-methylbenzamide Example368 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-methylphenyl!-2,3-dimethylbenzamideExample 369 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-methylphenyl!-3-fluoro-2-methylbenzamideExample 370 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-methylphenyl!-5-fluoro-2-methylbenzamideExample 371 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl!carbonyl!-3-methylphenyl!-4-fluoro-2-methylbenzamideExample 372 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-methylphenyl!-2-methylthiobenzamideExample 373 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-methylphenyl!-2-(trifluoromethoxy)benzamideExample 374 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-methylphenyl!-3-fluoro-2-methylbenzamideExample 375 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-5-fluoro-2-methylbenzamideExample 376 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-2-methylbenzamide Example377 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-2-chloro-4-fluorobenzamideExample 378 N- 4- (4,5-Dihydro-6H-isoxazolo 4,5-d!1!benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-2,3-dichlorobenzamideExample 379 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-methylbenzamide

To a mixture of 0.420 g of2,4,5,6-tetrahydro-2-methyl-6-(4-aminobenzoyl)pyrazolo 4,3-d!1!-benzazepine and 275 μl of triethylamine in 6 ml of methylene chlorideand 2 ml of dioxane is added a solution of 215 μl of 2-methylbenzoylchloride in 1.5 ml of dioxane. The reactants are stirred under argon for4.5 hours. The volatiles are evaporated in vacuo to a residue which isdissolved in methylene chloride and washed with 10% NaHCO₃ and brine.The organic layer is treated with activated carbon, dried with MgSO₄ andevaporated in vacuo to give 660 mg of a tan foam residue. The residue ispurified by column chromatography on silica gel by elution with 30%ethyl acetate-methylene chloride to give 590 mg of the desired productas white crystalline solid, m.p. 246°-248° C.; HR FABMS: (M+H)=437.1972.

The following examples are prepared as described for Example 379.

Example 380 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-chlorobenzamide Example 381 N-4- (4,5-Dihydro-2-methylpyrazolo 4,3 -d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2,4-dichlorobenzamide Example382 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2,3-dichlorobenzamide Example383 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-methyl-4-chlorobenzamideExample 384 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2,3-dimethylbenzamide Example385 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-methoxybenzamide Example 386N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-(trifluoromethoxy)benzamideExample 387 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2,4-dimethoxybenzamide Example388 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-methoxy-4-chlorobenzamideExample 389 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-(trifluoromethyl)benzamideExample 390 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-3-(trifluoromethyl)benzamideExample 391 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-(methylthio)benzamide Example392 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-4-fluoro-2-(trifluoromethyl)benzamideExample 393 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-fluoro-3-(trifluoromethyl)benzamideExample 394 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-chloro-4-fluorobenzamideExample 395 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-3-fluoro-2-methylbenzamideExample 396 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-5-fluoro-2-methylbenzamideExample 397 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-3-fluoro-5-(trifluoromethyl)benzamideExample 398 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-chloro-5-(methylthio)benzamideExample 399 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-methyl-3-thiophenecarboxamideExample 400 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-methyl-3-furanecarboxamideExample 401 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-chlorobenzeneacetamide Example402 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!phenyl!-2-methylbenzeneacetamide Example403 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!-3-chlorophenyl!-2-methylbenzamideExample 404 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!-3-chlorophenyl!-2,3-dimethylbenzamideExample 405 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!-3-chlorophenyl!-2,3-dichlorobenzamideExample 406 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!-3-chlorophenyl!-2,4-dichlorobenzamideExample 407 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!-3-chlorophenyl!-3-fluoro-2-methylbenzamideExample 408 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!-3-chlorophenyl!-5-fluoro-2-methylbenzamideExample 409 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!-3-chlorophenyl!-2-chloro-4-fluorobenzamideExample 410 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!-3-methylphenyl!-2-methylbenzamideExample 411 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!-3-methylphenyl!-2,3-dimethylbenzamideExample 412 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!-3-methylphenyl!-2-chloro-4-fluorobenzamideExample 415 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!-3-methylphenyl!-3-fluoro-2-methylbenzamideExample 414 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!-3-methylphenyl!-5-fluoro-2-methylbenzamideExample 415 N- 4- (4,5-Dihydro-2-methylpyrazolo 4,3-d!1!-benzazepin-6(2H)-yl)carbonyl!-3-methylphenyl!-2,4-dichlorobenzamideExample 416 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-2-methylbenzamide

To a solution of 0.216 mg of6,7-dihydro-2-methyl-7-(4-aminobenzoyl)-5H-pyrimido 5,4-d! 1!benzazepinein 6 ml of methylene chloride under argon is added 100 μl oftriethylamine followed by a solution of 94 μl of 2-methylbenzoylchloride in 1.5 ml of methylene chloride. The reaction mixture isstirred at room temperature for 18 hours, washed with water, saturatedNaHCO₃ and the separated organic layer treated with activated carbon andfiltered through MgSO₄. The filtrate is evaporated to a residue which isdissolved in ethyl acetate and evaporated in vacuo to give 300 mg of thedesired product as a pale yellow foam. HR FABMS: Exact Mass(M+H):449.1974.

The following compounds are prepared as described in Example 416.

Example 417 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-2,3-dimethylbenzamide Example 418 N-4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-2-chloro-4-fluorobenzamide Example419 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-2,4-dichlorobenzamide Example 420 N-4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-2,3-dichlorobenzamide Example 421 N-4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-3-fluoro-2-methylbenzamide Example422 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-2-methoxybenzamide Example 423 N- 4-(6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-5-fluoro-2-methylbenzamide Example424 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-2-(trifluoromethoxy)benzamideExample 425 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-2-methoxy-4-chlorobenzamide Example426 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-2-chloro-5-fluorobenzamide Example427 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-2-(trifluoromethyl)benzamide Example428 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-2-(methylthio)-benzamide Example 429N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!phenyl!-4-fluoro-2-methylbenzamide Example430 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-chlorophenyl!-2-methylbenzamide Example431 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-chlorophenyl!-2,3-dimethylbenzamideExample 432 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl-3-chlorophenyl!-3-fluoro-2-methylbenzamideExample 433 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-chlorophenyl!-5-fluoro-3-methylbenzamideExample 434 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-chlorophenyl!-2-chloro-4-fluorobenzamideExample 435 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-chlorophenyl!-2-chloro-5-fluorobenzamideExample 436 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-chlorophenyl!-2,3-dichlorobenzamideExample 437 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-chlorophenyl!-2-(trifluoromethoxy)benzamideExample 438 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-methoxyphenyl!-3-fluoro-2-methylbenzamideExample 439 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-methoxyphenyl!-5-fluoro-2-methylbenzamideExample 440 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-methylphenyl!-3-fluoro-2-methylbenzamideExample 441 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-methylphenyl!-5-fluoro-2-methylbenzamideExample 442 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-methylphenyl!-2,3-dichlorobenzamideExample 443 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-methylphenyl!-2-chloro-5-fluorobenzamideExample 444 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-methylphenyl!-2-chloro-4-fluorobenzamideExample 445 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-methylphenyl!-2,3-dimethylbenzamideExample 446 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-methylphenyl!-2-(trifluoromethyl)benzamideExample 447 N- 4- (6,7-Dihydro-2-methyl-5H-pyrimido 5,4-d!1!-benzazepin-7-yl)carbonyl!-3-methylphenyl!-2-(trifluoromethoxy)benzamideExample 448 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)yl)carbonyl!phenyl!-2-chlorobenzamide

To a solution of 385 mg of 2-chloro-benzoyl chloride in 6 ml ofmethylene chloride at 0° C. is added 0.6 g of10-(4-aminobenzoyl)-10,11-dihydrodibenz b,f!- 1,4!thiazepine followed by0.375 ml of triethylamine. The reaction mixture is stirred at roomtemperature for 18 hours. The reaction mixture is washed with 20 ml ofwater, 1N HCl, 1N Na₂ CO₃, water and dried over MgSO₄. The filtrate isevaporated in vacuo to give 0.7 g of yellowish solid which is purifiedby silica gel chromatography on thick layer plates by elution with 1:1ethyl acetate-hexane to give 0.3 g of the desired product, m.p.116°-119° C.

Example 449 N- 4- (Dibenz b,f!1,4!thiazepin-10(11H)-yl)carbonyl!phenyl!-2,4-dichlorobenzamide

To a solution of 452 mg of 2,4-dichlorobenzoyl chloride in 6 ml ofmethylene chloride is added 0.6 g of10-(4-aminobenzoyl)-10,11-dihydrodibenz b,f!- 1,4!thiazepine followed by0.375 ml of triethylamine. The reaction mixture is stirred at roomtemperature for 18 hours. The reaction mixture is washed with 20 ml ofwater, 1N HCl, 1N Na₂ CO₃, water and dried over MgSO₄. The filtrate isevaporated in vacuo to give 0.72 g of yellowish solid which is purifiedby silica gel chromatography on thick layer plates by elution with 1:1ethyl acetate-hexane to give 0.254 g of the desired product as ivorycrystals, m.p. 112°-115° C.

Example 450 5- 4-(2-Chlorophenyl)sulfonyl!amino!benzoyl!-6,11-dihydro-5H-dibenzb,e!azepine

A mixture of 0.13 g of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenzb,e!azepine, 0.21 g of 2-chlorobenzenesulfonyl chloride, 0.12 g oftriethylamine and 5 mg of N,N-dimethylaminopyridine in 2 ml of methylenechloride is stirred at room temperature for 18 hours. The mixture ispartitioned between 1N NaOH and ethyl acetate. The organic layer iswashed with 50% NH₄ Cl and brine, dried over Na₂ SO₄ and evaporated togive 0.26 g of the desired product as a yellow solid. MS(CI):663(M+H;C³⁵).

A solution of 0.22 g of the preceding compound in 5 ml oftetrahydrofuran is treated with 2 ml of 1N NaOH and 2 ml of methanol andstirred at room temperature for 1 hour. The organic solvents are removedin vacuo and the residue diluted with 15 ml of ethyl acetate and 5 ml ofwater. The organic extract is washed with 5 ml of 1N NaOH, brine anddried. (Na₂ SO₄) and evaporated in vacuo to give 0.19 g of yellow solidwhich is washed with diethylether-isopropyl ether to give 0.17 g ofbeige solid. MS(CI):489(M+H, Cl³⁵).

Example 451 6- 4-(2,4-Dichlorobenzoyl)amino!benzoyl!-5,6-dihydropyrazolo 4,3-d!1!benzazepine-2(4H)-acetic acid

To a stirred slurry of 0.477 g of 6- 4-(2,4-dichlorobenzoyl)amino!benzoyl!-5,6-dihydropyrazolo- 4,3-d!1!benzazepine-2(4H)-acetic acid, ethyl ester in 15 ml of ethyl alcoholis added 5 ml of tetrahydrofuran followed by 1.30 ml of 1M NaOH. Thereaction mixture is stirred at room temperature for 6 hours followed bythe addition of 0.750 ml of 2M HCl. The acidic reaction mixture isevaporated in vacuo, triturated with CHCl₃, combined, treated withactivated carbon, filtered through MgSO₄ and evaporated in vacuo to give0.380 mg of the desired product as a clear foam.

Example 452 Ethyl 6- 4-(2,4-dichlorobenzoyl)amino!benzoyl!-5,6-dihydropyrazolo 4,3-d!1!benzazpeine-2(4H)-acetate

To a stirred solution of 0.940 g of ethyl6-(4-aminobenzoyl)-5,6-dihydropyrazolo 4,3-d!1!benzazepine-2(4H)-acetate in 25 ml of methylene chloride is added 369μl of triethylamine followed by the dropwise addition of 373 μl of2,4-dichlorobenzoyl chloride in 3.5 ml of methylene chloride. Thereaction mixture is stirred at room temperature for 18 hours, washedwith water, saturated NaHCO₃, brine and the organic layer treated withactivated carbon, and filtered through MgSO₄. The filtrate isconcentrated in vacuo to a residue which is purified by flashchromatography on silica gel using 25% ethyl acetate in methylenechloride to give 380 mg of the desired product as white crystals, m.p.164°-167° C. The mother liquors are combined, evaporated in vacuo to aresidue which is dissolved in 25% ethyl acetate in chloroform to give535 mg of off-white solid, m.p. 160°-163.5° C.

Example 453 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-(2-methylpropoxy)benzamide

To a mixture of 0.62 g of 2-chloro-5-nitrobenzoic acid and 0.61 g oftriethylamine in 5 ml of methylene chloride is added 0.42 g ofisobutylchloroformate at 0° C. The mixture is warmed to room temperaturefor 30 minutes. A solution of 0.31 g of5-(4-aminobenzoyl)-6,7-dihydro-5H-dibenz b,d!azepine in 1 ml ofmethylene chloride is added followed by 10 mg ofN,N-dimethylaminopyridine and 1.0. ml of toluene is added. The mixtureis heated at 100° C. for 48 hours. The room temperature reaction mixtureis diluted with 15 ml of ethyl acetate and washed with 1N HCl, 1N NaOH,brine and dried (Na₂ SO₄) and evaporated in vacuo to a residue. Theresidue is purified by column chromatography on silica gel by elutionwith 1:2 ethyl acetate-hexane to give 0.28 g of the desired product as ayellow solid. MS(CI):536(M+H).

Example 454 N- 4- (6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)carbonyl!phenyl!-2-(dimethylamino)acetamide

To a solution of 0.31 g of 5-(4-aminobenzoyl)-6,7-dihydro-5H-dibenzb,e!azepine in 5 ml of methylene chloride is added 0.53 g of Na₂ CO₃followed by 0.31 g of N,N-dimethylglycyl chloride. The mixture isstirred at room temperature for 20 hours. The mixture is quenched withwater, extracted with ethyl acetate and the organic layer dried (Na₂SO₄) and concentrated in vacuo to give 0.39 g of yellow foam. The yellowfoam is treated with 15 ml of hydrochloric acid and the suspensionwashed with ethyl acetate. The aqueous suspension is made alkaline with5N NaOH and extracted with 30 ml of ethyl acetate. The organic layer iswashed with brine, dried (Na₂ SO₄) and evaporated to give 0.32 g of thedesired product as an off-white solid. MS(CI): 400(M+H). A sample istreated with anhydrous HCl to give the hydrochloride salt. MS(CI):400(M+H-HCl).

Example 455 N- 4-(4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!phenyl!-2,4-dichlorobenzamide

To a stirred solution of 0.235 g of5,6-dihydro-2-methyl-6-(4-aminobenzoyl)-4H-thiazolo 5,4-d!-1!benzazepine in 6 ml of methylene chloride under argon is added 107 μlof triethylamine followed by the dropwise addition of 109 μl of2,4-dichlorobenzoyl chloride in 1 ml of methylene chloride. Stirring iscontinued at room temperature for 18 hours. The reaction mixture iswashed with H₂ O, saturated NaHCO₃ and brine. The organic layer istreated with activated carbon, filtered through MgSO₄ and the filtrateevaporated in vacuo to a residue which is chromatographed on silica gelby elution with 15% ehtyl acetate in methylene chloride to give 330 mgof the desired product as a tan glass.

Example 456 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!phenyl!-2-methylbenzamide

A mixture of 400 mg of 4,10-dihydro-5H-thieno 3,2-c! 1!benzazepine and700 mg of 4- (2-methylbenzoyl)amino!benzoyl chloride is stirred in 30 mlof methylene chloride in the presence of 3 ml of triethylamine for 8hours. The volatiles are removed in vacuo to give a residue which ispartitioned between chloroform and water. The organic layer is dried(Na₂ SO₄) and the filtrate evaporated in vacuo to give a residue whichis purified by column chromatography on silica gel by elution with 30%ethyl acetate-hexane to give 543 mg of the desired product. M+1=439.

Example 457 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!phenyl!-2,3-dichlorobenzamide

A mixture of 200 mg of 9,10-dihydro-4H-thieno 2,3-c! 1! and 350 mg of 4-(2-methylbenzoyl)-amino!benzoyl chloride is stirred in 30 ml ofmethylene chloride in the presence of 2 ml of triethylamine for 8 hours.The volatiles are removed in vacuo to give a residue which ispartitioned between water and chloroform. The organic layer is dried(Na₂ SO₄) and the filtrate evaporated in vacuo to give a residue whichis purified by column chromatography on silica gel by elution with 30%ethyl acetate-hexane to give 266 mg of the desired product. M+1=494.

Example 458 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!phenyl!-2-methylbenzamide

A mixture of 400 mg of 9,10-dihydro-4H-thieno 2,3-c! 1!benzazepine and600 mg of 4- (2-methylbenzoyl)amino!benzoyl chloride is stirred in 30 mlof methylene chloride in the presence of 3 ml of triethylamine for 8hours. The volatiles are removed in vacuo to give a residue which ispartitioned between water and chloroform. The organic layer is dried(Na₂ SO₄) and the filtrate evaporated in vacuo to give a residue whichis purified by column chromatography on silica gel by elution with 30%ethyl acetate-hexane to give 518 mg of the desired product. M+1=439.

The following examples are prepared using conditions of Example 456.

Example 459 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2,3-dimethylbenzamideExample 460 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2,5-dimethylbenzamideExample 461 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2-methoxybenzamide Example462 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2-(trifluoromethoxy)benzamideExample 463 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2-methoxy-4-chlorobenzamideExample 464 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2-(methylthio)benzamideExample 465 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2,3-dichlorobenzamideExample 466 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-thiophenecarboxamideExample 467 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-3-methyl-2-thiophenecarboxamideExample 468 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2-chlorobenzeneacetamideExample 469 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-3-fluoro-2-methylbenzamideExample 470 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-5-fluoro-2-methylbenzamideExample 471 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2,3-difluorobenzamideExample 472 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-4-fluoro-2-methylbenzamideExample 473 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2,3,5-trichorobenzamideExample 474 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2-fluoro-5-(trifluoromethyl)benzamideExample 475 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2-fluoro-6-(trifluoromethyl)benzamideExample 476 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-3-fluoro-5-(trifluoromethyl)benzamideExample 477 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2,6-dichlorobenzamideExample 478 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2-(trifluoromethyl)benzamideExample 479 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2-chloro-4-fluorobenzamideExample 480 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-chlorophenyl!-2-chloro-5-fluorobenzamideExample 481 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-fluorophenyl!-3-fluoro-2-methylbenzamideExample 482 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-fluorophenyl!-5-fluoro-2-methylbenzamideExample 483 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-fluorophenyl!-2-chloro-4-fluorobenzamideExample 484 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-methylphenyl!-2-methylbenzamide Example485 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-methylphenyl!-3-fluoro-2-methylbenzamideExample 486 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-methylphenyl!-5-fluoro-2-methylbenzamideExample 487 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-methylphenyl!-2-chloro-4-fluorobenzamideExample 488 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-methylphenyl!-2-chloro-5-fluorobenzamideExample 489 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-methylphenyl!-2,3-dichlorobenzamideExample 490 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-methylphenyl!-2-chloro-4-fluorobenzamideExample 491 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-methylphenyl!-2,3-dimethylbenzamideExample 492 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-methylphenyl!-2,4-dichlorobenzamideExample 493 N- 4- (4,10-Dihydro-5H-thieno 3,2-c!1!benzazepin-5-yl)carbonyl!-3-methylphenyl!-2-(methylthio)benzamide

The following examples are prepared using conditions of Example 458.

Example 494 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2-chlorobenzamide Example495 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2-methylbenzamide Example496 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2,3-dichlorobenzamideExample 497 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2,3-dimethylbenzamideExample 498 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2,4-dichlorobenzamideExample 499 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2-methoxybenzamide Example500 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2-(trifluoromethoxy)benzamideExample 501 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2-methoxy)-4-chlorobenzamideExample 502 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2,6-dichlorobenzamideExample 503 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2-(trifluoromethyl)benzamideExample 504 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2-(methylthio)benzamideExample 505 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-3-methyl-2-thiophenecarboxamideExample 506 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-thiophenecarboxamideExample 507 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2-methylbenzeneacetamideExample 508 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2-(trifluoromethyl)-4-fluorobenzamideExample 509 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2,5-dimethylbenzamideExample 510 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-3-fluoro-2-methylbenzamideExample 511 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-5-fluoro-2-methylbenzamideExample 512 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2-chloro-4-fluorobenzamideExample 513 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2-chloro-5-fluorobenzamideExample 514 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-2-fluoro-5-(trifluoromethyl)benzamideExample 515 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-chlorophenyl!-3-fluoro-5-(trifluoromethyl)benzamideExample 516 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-fluorophenyl!-2-methylbenzamide Example517 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-fluorophenyl!-3-fluoro-2-methylbenzamideExample 518 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-fluorophenyl!-5-fluoro-2-methylbenzamideExample 519 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-2-methylbenzamide Example520 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-2,3-dimethylbenzamideExample 521 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-2,5-dimethylbenzamideExample 522 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-3-fluoro-2-methylbenzamideExample 523 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-5-fluoro-2-methylbenzamideExample 524 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-2,3-dichlorobenzamideExample 525 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-2,4-dichlorobenzamideExample 526 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-2-chloro-4-fluorobenzamideExample 527 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-2-chloro-5-fluorobenzamideExample 528 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-2-fluoro-5-(trifluoromethyl)benzamideExample 529 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-2-methyl-4-chlorobenzamideExample 530 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-2-methoxybenzamide Example531 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-2-(trifluoromethoxy)benzamideExample 532 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-2-(trifluoromethyl)benzamideExample 533 N- 4- (4,10-Dihydro-9H-thieno 2,3-c!1!benzazepin-9-yl)carbonyl!-3-methylphenyl!-2-(thiomethyl)benzamideExample 534 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!phenyl!-5-fluoro-2-methylbenzamide

To a stirred solution of 0.235 g of5,6-dihydro-2-methyl-6-(4-aminobenzoyl)4H-thiazolo 5,4-d! 1!-benzazepinein 6 ml of methylene chloride under argon is added 107 μl oftriethylamine followed by the dropwise addition of2-methyl-5-fluorobenzoyl chloride in 1 ml of methylene chloride.Stirring is continued at room temperature for 18 hours. The reactionmixture is washed with H₂ O, saturated NaHCO₃ and brine. The organiclayer is treated with activated carbon, filtered through MgSO₄ and thefiltrate evaporated in vacuo to a residue which is chromatographed onsilica gel by elution with 15% ethyl acetate in methylene chloride togive 300 mg of the desired product as a white solid; Anal. Calc'd forC₂₇ H₂₂ FN₃ O₂ S: C,68.8; H,4.7; N,8.9; F,4.0; S,6.8 Found: C,67.7;H,4.6; N,8.5; F,3.7; S,6.4.

The following examples are prepared using the conditions of Example 534with the appropriately substituted aroyl chloride.

Example 535 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2,3-dichlorobenzamideExample 536 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methyl-4-chlorobenzamideExample 537 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methoxybenzamide Example538 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methoxy-4-chlorobenzamideExample 539 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-(trifluoromethoxy)benzamideExample 540 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-(trifluoromethyl)benzamideExample 541 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2,6-dichlorobenzamideExample 542 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2,3-dimethylbenzamideExample 543 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2,5-dimethylbenzamideExample 544 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-3-(trifluoromethyl)benzamideExample 545 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-(methylthio)benzamideExample 546 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-thiophenecarboxamideExample 547 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-3-methyl-2-thiophenecarboxamideExample 548 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-3-methyl-2-furanecarboxamideExample 549 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methylbenzeneacetamideExample 550 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-3-fluoro-3-methylbenzamideExample 551 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-5-fluoro-2-methylbenzamideExample 552 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-4-fluoro-2-methylbenzamideExample 553 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-fluoro-4-(trifluoromethyl)benzamideExample 554 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-3-fluoro-5-(trifluoromethyl)benzamideExample 555 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-chloro-4-fluorobenzamideExample 556 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-chloro-5-fluorobenzamideExample 557 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-chlorophenyl!-4-fluoro-2-(trifluoromethyl)benzamideExample 558 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-fluorophenyl!-2-chloro-4-fluorobenzamideExample 559 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-fluorophenyl!-3-fluoro-2-methylbenzamideExample 560 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-fluorophenyl!-5-fluoro-2-methylbenzamideExample 561 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-fluorophenyl!-2-chloro-4-fluorobenzamideExample 562 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methylphenyl!-3-fluoro-2-methylbenzamideExample 563 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methylphenyl!-2-methylbenzamide Example564 N- 4- (4,5-Dihydro-2-methyl-6Hthiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methylphenyl!-5-fluoro-2-methylbenzamideExample 565 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methylphenyl!-2-chloro-5-fluorobenzamideExample 566 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methylphenyl!-2,3-dimethylbenzamideExample 567 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methylphenyl!-2,5-dimethylbenzamideExample 568 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methylphenyl!-2,4-dichlorobenzamideExample 569 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methylphenyl!-2-methoxy-4-chlorobenzamideExample 570 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methylphenyl!-2-(trifluoromethoxy)benzamideExample 571 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methylphenyl!-2-(methylthio)benzamideExample 572 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-2-methylbenzamide Example573 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-2,4-dichlorobenzamideExample 574 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-2-chloro-4-fluorobenzamideExample 575 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-3-fluoro-2-methylbenzamideExample 576 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-5-fluoro-2-methylbenzamideExample 577 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-2,3-dimethylbenzamideExample 578 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-2-methylbenzeneacetamideExample 579 N- 4- (4,5-Dihydro-2-methyl-6H-thiazolo 5,4-d!1!-benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-2-chlorobenzeneacetamideExample 580 6,11-Dihydro-5- 4- 3-methylbutanoyl)amino!benzoyl!-5H-dibenzb,e!azepine

To a stirred solution of 0.16 g of6,11-dihydro-5-(4-aminobenzoyl)-5H-dibenz b,e!azepine in 2 ml ofmethylene chloride is added 0.10 g of triethylamine followed by 0.09 gof iso-valeryl chloride. After stirring at room temperature for 2 hours,the reaction mixture is evaporated in vacuo to a residue. The residue isextracted with ethyl acetate-methylene chloride, washed with brine,dried (Na₂ SO₄), filtered through hydrous magnesium silicate andevaporated in vacuo to a residue which is stirred with ether-hexanes togive 0.21 g of light yellow solid. MS (CI): 399 (M+H).

Example 581 Ethyl 6- 4-(5-fluoro-2-methylbenzoyl)amino!benzoyl!-4,5-dihydro-6H-thieno 3,2-d!1!benzazepine-2-carboxylate

(a) To 20 ml of N,N-dimethylformamide (cooled to 0° C.) is addeddropwise (with rapid stirring) 1.80 ml (19.4 mmol) of phosphorylchloride. After stirring for 10 minutes, 2.0 g (6.45 mmol) of1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one is added.The mixture is stirred at 0° C. for 1 hour and at 80° C. for 3.5 hoursand poured into 70 ml of cold aqueous 20%. sodium acetate. Additionalwater is added and the solid is filtered off, washed with water anddried under vacuum. The2,3-dihydro-5-chloro-1-(4-nitrobenzoyl)-1H-1-benzazepine-4-carboxaldehyde(2.15 g) is stored at 0° C. and used in the next step without furtherpurification.

(b) To a slurry of 0.240 g (6.01 mmol) of sodium hydride (60% in oil) in20 ml of N,N-dimethylformamide, chilled in an ice bath, is added 0.656ml (6.01 mmol) of ethyl 2-mercaptoacetate. The mixture is stirred for 10minutes and a slurry of 2.14 g (6.01 mmol) of2,3-dihydro-5-chloro-1-(4-nitrobenzoyl)-1H-1-benzazepine-4-carboxaldehydein 6 ml of N,N-dimethylformamide is added dropwise. The mixture isstirred at room temperature overnight and then concentrated under highvacuum. The residue is partitioned between chloroform and water and theorganic layer separated. The aqueous layer is extracted (twice) withchloroform and the organic layer and extracts combined and dried (Na₂SO₄). The solvent is removed and the residue chromatographed on silicagel with dichloromethane as eluent (2 liter) and then with 4% ethylacetate in dichloromethane as eluent. Fractions containing product arecombined and the solvent removed under vacuum to give 2.1 g of ethyl4,5-dihydro-6-(4-nitrobenzoyl)-6H-thieno 3,2-d!1!benzazepine-2-carboxylate as a yellow foam.

(c) A mixture of ethyl (4,5-dihydro-6-(4-nitrobenzoyl)-6H-thieno 3,2-d!1!benzazepine-2-carboxylate (0.800 g) and 2.14 g of stannous chloridedihydrate in 36 ml of ethanol is refluxed for 1 hour, cooled to roomtemperature and diluted with ice water. The mixture is made basic with10% sodium bicarbonate and stirred 3.8 hours. The mixture is extractedwith chloroform and the extracts combined, treated with activated carbonand filtered through anhydrous magnesium sulfate. The filtrate isconcentrated under vacuum to give 0.690 g of ethyl4,5-dihydro-6-(4-aminobenzoyl)-6H-thieno 3,2-d!1!benzazepine-2-carboxylate as a tan foam: mass spectrum (CI) 393 (MH⁺).

(d) To a solution of the preceding product (0.660 g) in 15 ml ofdichloromethane is added 0.187 g of triethylamine and then a solution of0.318 g of 5-fluoro-2-methylbenzoyl chloride in 2 ml of dichloromethaneis added. The mixture is stirred overnight and then washed with H₂ O,10% HCl, 10% NaHCO₃ and dried (MgSO₄). The solvent is removed and theresidue chromatographed on silica gel with ethyl acetate-dichloromethane(1:9) as eluent to give 0.70 g of ethyl 6- 4-(5-fluoro-2-methylbenzoyl)amino!benzoyl!-4,5-dihydro-6H-thieno 3,2-d!1!benzazepine-2-carboxylate as a tan foam; mass spectrum (highresolution FAB) 529.1592 (MH⁺).

Example 582 6- 4- (5-Fluoro-2-methylbenzoyl)amino!benzoyl!1!-4,5-dihydro-6H-thieno 3,2-d! 1!benzazepine-2-carboxylic acid

A slurry of 0.43 g of ethyl 6- 4-(5-fluoro-2-methylbenzoyl)amino!benzoyl!-4,5-dihydro-6H-thieno- 3,2-d!1!benzazepine-2-carboxylate in 5 ml of methanol, 2 ml of tetrahydrofuranand 1.30 ml of 1M NaOH is stirred overnight. To the solution is added 2Mhydrochloric acid until the mixture is acidic. The volatiles are removedunder vacuum and the residue diluted with water. The mixture isextracted with chloroform and the extracts combined and thenconcentrated under vacuum. Methanol is added (several times) and thesolvent removed to give a solid. The solid is triturated with diethylether to give 0.38 g of white crystals, m.p. 290°-292° C.; mass spectrum(high resolution-FAB) 501.1255 (MH⁺).

Example 583 N- 4- (4,5-Dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!phenyl!-2-methyl-3-fluorobenzamide

(a) A mixture of 0.80 g of ethyl4,5-dihydro-6-(4-nitrobenzoyl)-6H-thieno 3,2-d!1!-benzazepine-2-carboxylate in 25 ml of ethanol, 6 ml oftetrahydrofuran and 3.13 ml of 1M sodium hydroxide is stirred at roomtemperature for 22 hours. The mixture is acidified with 2 ml of 2M HCland the solvents removed. The residue is dried under vacuum andextracted several times with CHCl₃ --CH₃ OH (1:1). The extracts arecombined and the solvent removed to give 0.72 g of4,5-dihydro-6-(4-nitro-benzoyl)-6H-thieno 3,2-d!1!benzazepine-2-carboxylic acid as a yellow solid; mass spectrum (CI)395 (MH⁺).

(b) A mixture of 0.500 g of the preceding compound and 50 mg of copperpowder in 7.5 ml of quinoline under argon is heated at 100°-105° C. for1.5 hours. To the cooled mixture is added methanol and the mixture isfiltered through diatomaceous earth. The filtrate is evaporated and theresidue dissolved in dichloromethane and the solution washed (twice)with 6M HCl and dried (MgSO₄). The solvent is removed to give a tansolid. This procedure was repeated three times to give 0.87 g of4,5-dihydro-6-(4-nitrobenzoyl)-6H-thieno 3,2-d! 1!benzazepine as tancrystals; mass spectrum (CI) 351 (MH⁺).

(c) A mixture of 0.570 g of the preceding compound and 1.84 g ofSnCl₂.2H₂ O in 26 ml of ethanol under argon is refluxed for 1 hour andcooled to room temperature. Ice water is added and 10% NaHCO₃ added tobring the pH to 8. After stirring for 4 hours, the mixture is extractedwith chloroform (4 times). The combined extracts are dried (MgSO₄) andthe solvent removed to give a brown oil. The product oil from twobatches is combined and chromatographed on silica gel withdichloromethane as eluent and then dichloromethane-ethyl acetate (9:1)as eluent. Fraction containing product are combined and the solventremoved to give 0.69 g of 4,5-dihydro-6-(4-aminobenzoyl)-6H-thieno3,2-d! 1!benzazepine as a tan foam; mass spectrum (CI) 321 (MH⁺).

(d) To a mixture of 0.310 g of the preceding compound and 147 mg oftriethylamine in 7 ml of dichloromethane is added 0.249 g of2-methyl-3-fluorobenzoyl chloride in 1 ml of dichloromethane. Thesolution is stirred overnight and water added. The water is removed(solid at interface) and the organic layer washed with 10% HCl and then10% NaHCO₃. The organic layer (containing solid) is filtered and thesolid washed with dichloromethane. The filtrate is dried (MgSO₄) and thesolvent removed to give a solid. The two crops of solid are trituratedwith cold dichloromethane to give crystals. The filtrate is filteredthrough a short silica gel column with CH₂ Cl₂ as eluent (discard) andthen the silica gel is washed with ethyl acetate-dichloromethane (1:9)to give (on evaporation of solvent) 0.38 g of a white solid; massspectrum (FAB-high resolution) 457.1388 (M+H).

Example 584 N- 4- (2-Chloro-4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!phenyl!-2-methyl-3-fluorobenzamide

To a solution of 0.457 g (1.0 mmol) of N- 4- (4,5-dihydro-6H-thieno3,2-d! 1!benzazepin-6-yl)carbonyl!phenyl!-2-methyl-3-fluorobenzamide in25 ml of ethyl acetate is added 1.0 mmol of N-chlorosuccinimide. Themixture is stirred overnight and filtered. The filtrate is washed withwater, 1N HCl, 1M NaHCO₃, H₂ O and dried (Na₂ SO4). The solvent isremoved to give the product as a solid.

Example 585 N- 4- (4,5-Dihydro-6H-thieno 3,2=d!1!benzazepin-6-yl)carbonyl!phenyl!-2-methyl-5-fluorobenzamide

To a mixture of 0.310 g of 4,5-dihydro-6-(4-aminobenzoyl)-6H-thieno3,2-d! 1!benzazepine and 150 mg of triethylamine in 7 ml ofdichloromethane is added 0.249 g of 2-methyl-5-fluorobenzoyl chloride in2 ml of dichloromethane. The mixture is stirred overnight and thesolvent removed. To the residue is added ethyl acetate and the mixturewashed with H₂ O, 10% HCl, 10% NaHCO₃ and dried (Na₂ SO₄). The solventis removed to give the product as a solid. The solid is chromatographedon silica gel with dichloromethane-ethyl acetate (95:5), thendichloromethane-ethyl acetate (9:1) as eluent. The fraction containingproduct is collected and the solvent removed to give 0.40 g of a tanfoam; mass spectrum (high resolution FAB) 457:1388 (M+H).

We claim:
 1. A compound of the formula: ##STR167## wherein; Y is abond;A-B is ##STR168## R₁ is H, halogen (Cl, F, Br, I), OH, --S--loweralkyl (C₁ -C₃), --SH, --SO lower alkyl (C₁ -C₃), --SO₂ lower alkyl (C₁-C₃), --CO lower alkyl (C₁ -C₃), --CF₃, lower alkyl (C₁ -C₃), --O loweralkyl (C₁ -C₃), --NO₂, --NH₂, --NHCO lower alkyl (C₁ -C₃), --N-- loweralkyl (C₁ -C₃)!₂, SO₂ NH₂, --SO₂ NH lower alkyl (C₁ -C₃), or --SO₂ Nlower alkyl (C₁ -C₃)!₂ ; R₂ is selected from H, Cl, Br, I, F, --OH,lower alkyl (C₁ -C₃), or --O lower alkyl (C₁ -C₃); or R₁ and R₂ takentogether are methylenedioxy or ethylenedioxy; R₃ is the moiety##STR169## wherein Ar is a moiety selected from the group ##STR170## R₅is H, --CH₃, --C₂ H₅, Cl, Br, F, --O--CH₃, or --O--C₂ H₅ ; R₆ isselected from: ##STR171## wherein cycloalkyl is defined as C₃ -C₆cycloalkyl, cyclohexenyl or cyclopentenyl; n is 0-2; and wherein Ar' isselected from the moieties: ##STR172## wherein R_(a) and R_(b) areindependently selected from H, --CH₃, or --C₂ H₅ ; R₇ is H, --CH₃, --C₂H₅, Cl, Br, F, --O--CH₃, --O--C₂ H₅ or --CF₃ ; R₈ and R₉ areindependently selected from hydrogen, lower alkyl (C₁ -C₃), O-loweralkyl (C₁ -C₃), S-lower alkyl (C₁ -C₃), --CF₃, --CN, --OH, --SCF₃,--OCF₃, halogen, NO₂, amino, or --NH-lower alkyl (C₁ -C₃); W' isselected from O, S, NH, N-lower alkyl (C₁ -C₃), --NCO-lower alkyl (C₁-C₃), or NSO₂ -lower alkyl (C₁ -C₃); the moiety ##STR173## represents afused thiophene ring or fused substituted thiophene ring optionallysubstituted by one or two substituents selected from (C₁ -C₃) loweralkyl, halogen, formyl, (C₁ -C₃) lower alkoxy, (C₁ -C₃) loweralkoxycarbonyl, --CO₂ H, a moiety of the formula: ##STR174## or apharmaceutically acceptable salt, ester or prodrug thereof.
 2. Thecompound according to claim 1, N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)phenyl!-2-methyl-3-fluorobenzamide.
 3. The compoundaccording to claim 1, N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)phenyl!-2-methylbenzamide.
 4. The compound accordingto claim 1, N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)phenyl!-2-methyl-5-fluorobenzamide.
 5. The compoundaccording to claim 1, N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-fluorobenzamide.6. The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno3,2-d! 1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methylbenzamide. 7.The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methyl-5-fluorobenzamide.8. The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno3,2-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-chloro-5-fluorobenzamide.9. The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno3,2-d!1!benzazepin-6-yl)-3,6-dichlorophenyl!-2-methyl-5-fluorobenzamide. 10.The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)-3-chlorophenyl!-2-(methylthio)-5-fluorobenzamide. 11.The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)phenyl!-2-chloro-5-fluorobenzamide.
 12. The compoundaccording to claim 1, N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-chlorobenzamide.13. The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno3,2-d! 1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-chlorobenzamide.14. The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno3,2-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methoxy-5-fluorobenzamide.15. The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno3,2-d!1!benzazepin-6-yl)carbonyl!-3-chlorophenyl!-2-chloro-4-fluorobenzamide.16. The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno 3,2-d! 1!benzazepin-6-yl)-3-methylphenyl!-2-methyl-3-fluorobenzamide. 17.The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)-3-methoxyphenyl!-2-methylbenzamide.
 18. The compoundaccording to claim 1, N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)-3-methylphenyl!-2-methyl-5-fluorobenzamide.
 19. Thecompound according to claim 1, N- 4- (4,5-dihydro-6H-thieno 3,2-d!1!benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-2-methyl-3-fluorobenzamide.20. The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno3,2-d! 1!benzazepin-6-yl)carbonyl!-3-fluorophenyl!-2-methylbenzamide.21. The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno3,2-d!1!benzazepin-6-yl)carbonyl!-3-methoxyphenyl!-2-methyl-5-fluorobenzamide.22. The compound according to claim 1, N- 4- (4,5-dihydro-6H-thieno3,2-d!1!benzazepin-6-yl)carbonyl!-3-methylphenyl!-2-chloro-5-fluorobenzamide.23. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a!3!benzazepin-4-yl)carbonyl!-3-chlorophenyl!-2-methyl-5-fluorobenzamide.24. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a!3!benzazepin-4-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-fluorobenzamide.25. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a!3!benzazepin-4-yl)carbonyl!-3-chlorophenyl!-2-chloro-5-fluorobenzamide.26. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a!3!benzazepin-4-yl)carbonyl!-3-chlorophenyl!-2,5-dichlorobenzamide. 27.The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-phenyl!-2-methyl-5-fluorobenzamide.
 28. Thecompound according to claim 1, N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-phenyl!-2-methyl-3-fluorobenzamide.
 29. Thecompound according to claim 1, N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-methylphenyl!-2-methyl-5-fluorobenzamide.30. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a!3!benzazepin-4-yl)carbonyl!-3-methylphenyl!-2-methyl-3-fluorobenzamide.31. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a!3!benzazepin-4-yl)carbonyl!-3-methylphenyl!-2-chloro-5-fluorobenzamide.32. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a!3!benzazepin-4-yl)carbonyl!-3-methylphenyl!-2,5-dichlorobenzamide. 33.The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno 2,3-a!3!benzazepin-4-yl)carbonyl!-3-methoxyphenyl!-2-methyl-5-fluorobenzamide.34. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a!3!benzazepin-4-yl)carbonyl!-3-methoxyphenyl!-2-methyl-3-fluorobenzamide.35. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a!3!benzazepin-4-yl)carbonyl!-3,6-dimethylphenyl!-2-methyl-5-fluorobenzamide.36. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a!3!benzazepin-4-yl)carbonyl!-3,6-dimethylphenyl!-2-methyl-3-fluorobenzamide.37. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a!3!benzazepin-4-yl)carbonyl!-3-chlorophenyl!-2-chloro-4-fluorobenzamide.38. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a!3!benzazepin-4-yl)carbonyl!-3-chlorophenyl!-2-chloro-6-fluorobenzamide.39. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a! 3!benzazepin-4-yl)carbonyl!-phenyl!-2-methoxy-5-fluorobenzamide.40. The compound according to claim 1, N- 4- (5,6-dihydro-4H-thieno2,3-a!3!benzazepin-4-yl)carbonyl!-phenyl!-2-(methylthio)-5-fluorobenzamide.41. A pharmaceutical composition useful for treating disease in a mammalcharacterized by excess renal reabsorption of water, the pharmaceuticalcomposition comprising an effective amount of a compound of claim 1, ora pharmaceutically acceptable salt, ester or prodrug form thereof, and asuitable pharmaceutical carrier.
 42. The pharmaceutical composition ofclaim 41 wherein the disease in a mammal characterized by excess renalreabsorption of water is congestive heart failure, nephrotic syndrome,hyponatremia, coronary vasospasm, cardiac ischemia, renal vasospasm,liver cirrhosis, brain edema, cerebral ischemia, or cerebralhemorrhage-stroke.
 43. A method for treating disease in a mammalcharacterized by excess renal reabsorption of water, the methodcomprising administering to a mammal in need thereof an effective amountof a compound of claim 1, or a pharmaceutically acceptable salt, esteror prodrug form thereof, and a suitable pharmaceutical carrier.
 44. Themethod of claim 43 wherein the disease in a mammal characterized byexcess renal reabsorption of water is congestive heart failure,nephrotic syndrome, hyponatremia, coronary vasospasm, cardiac ischemia,renal vasospasm, liver cirrhosis, brain edema, cerebral ischemia, orcerebral hemorrhage-stroke.